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neurazenx
CONTACTABOUTPURCHASEOUR BLOGPRODUCTSHOME

Neurazenx® 

clinical studies

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CONTACTABOUTPURCHASEOUR BLOGPRODUCTSHOME

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CLINICAL RESEARCH⌄CLINICAL RESEARCH⌄

FOR HEALTHCARE PROFESSIONALS

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Our products are 100% natural gluten-free, and GMO-free

Non-GMO and Gluten-Free

The highest quality vitamins, minerals, herbs, and supplements packed into one convenient nerve support formula. It’s the 1st daily supplement for nerve function and health.

14 pharmaceutical-grade ingredients in every capsule

This high-potency nutraceutical nerve health formula features ingredients proven to help improve nerve damage associated with diabetes, fibromyalgia, shingles, trauma, and lupus.

Improve nerve function

Physician and Pharmacist formulated, using pharmaceutical-grade ingredients, in an FDA-registered facility, and following Good Manufacturing Practice (GMP) to ensure our products are of the highest quality and purity.

Made in the USA

Ingredients include: Benfotiamine, Turmeric, N-acetyl cysteine (NAC), Alpha lipoic acid (ALA), L-Arginine, N-acetyl L-carnitine (ALC), Moringa oleifera, Vitamin C, Vitamin D3, Vitamin B12, Vitamin B2, Vitamin B6, Vitamin B9, Vitamin E, and Magnesium.

Powerful, proprietary herbal synergistic blend

R-Alpha-Lipoic Acid

"Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial Ziegler D, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006 Nov;29(11):2365-70. PubMed PMID: 17065669. OBJECTIVE: The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients' global assessment of efficacy. RESULTS: Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (>/=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients' global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. CONCLUSIONS: Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio."


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"Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy Ziegler D, Gries FA. Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes. 1997 Sep;46 Suppl 2:S62-6. Review. PubMed PMID: 9285502. Antioxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes, providing a rationale for a potential therapeutic value in diabetic patients. The effects of the antioxidant alpha-lipoic acid (thioctic acid) were studied in two multicenter, randomized, double-blind placebo-controlled trials. In the Alpha-Lipoic Acid in Diabetic Neuropathy Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. The total symptom score (TSS) (pain, burning, paresthesia, and numbness) in the feet decreased significantly from baseline to day 19 in ALA 1,200 and ALA 600 vs. PLAC. Each of the four individual symptom scores was significantly lower in ALA 600 than in PLAC after 19 days (all P < 0.05). The total scale of the Hamburg Pain Adjective List (HPAL) was significantly reduced in ALA 1,200 and ALA 600 compared with PLAC after 19 days (both P < 0.05). In the Deutsche Kardiale Autonome Neuropathie Studie, patients with NIDDM and cardiac autonomic neuropathy diagnosed by reduced heart rate variability were randomly assigned to treatment with a daily oral dose of 800 mg alpha-lipoic acid (ALA) (n = 39) or placebo (n = 34) for 4 months. Two out of four parameters of heart rate variability at rest were significantly improved in ALA compared with placebo. A trend toward a favorable effect of ALA was noted for the remaining two indexes. In both studies, no significant adverse events were observed. In conclusion, intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is safe and effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in NIDDM."


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"Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy Nagamatsu M, et al. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care 1995 18 1160–1167. OBJECTIVE To determine whether lipoic acid (LA) will reduce oxidative stress in diabetic peripheral nerves and improve neuropathy. RESEARCH DESIGN AND METHODS We used the model of streptozotocin-induced diabetic neuropathy (SDN) and evaluated the efficacy of LA supplementation in improving nerve blood flow (NBF), electrophysiology, and indexes of oxidative stress in peripheral nerves affected by SDN, at 1 month after onset of diabetes and in age-matched control rats. LA, in doses of 20, 50, and 100 mg/kg, was administered intraperitoneally five times per week after onset of diabetes. RESULTS NBF in SDN was reduced by 50% LA did not affect the NBF of normal nerves but improved that of SDN in a dose-dependent manner. After 1 month of treatment, LA-supplemented rats (100 mg/kg) exhibited normal NBF. The most sensitive and reliable indicator of oxidative stress was reduction in reduced glutathione, which was significantly reduced in streptozotocin-induced diabetic and alpha-tocopherol-deficient nerves; it was improved in a dose-dependent manner in LA-supplemented rats. The conduction velocity of the digital nerve was reduced in SDN and was significantly improved by LA. CONCLUSIONS These studies suggest that LA improves SDN, in significant part by reducing the effects of oxidative stress. The drug may have potential in the treatment of human diabetic neuropathy."


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"Alpha-Lipoic Acid and Diabetic Neuropathy Vallianou N, Evangelopoulos A, Koutalas P. Alpha-Lipoic Acid and Diabetic Neuropathy. The Review of Diabetic Studies : RDS. 2009;6(4):230-236. doi:10.1900/RDS.2009.6.230. Diabetic neuropathy presents a major public health problem. It is defined by the symptoms and signs of peripheral nerve dysfunction in diabetic patients, in whom other causes of neuropathy have been excluded. Pathogenetic mechanisms that have been implicated in diabetic neuropathy are: a) increased flux through the polyol pathway, leading to accumulation of sorbitol, a reduction in myo-inositol, and an associated reduced Na+-K+-ATPase activity, and b) endoneurial microvascular damage and hypoxia due to nitric oxide inactivation by increased oxygen free radical activity. Alpha-lipoic acid seems to delay or reverse peripheral diabetic neuropathy through its multiple antioxidant properties. Treatment with alpha-lipoic acid increases reduced glutathione, an important endogenous antioxidant. In clinical trials, 600 mg alpha-lipoic acid has been shown to improve neuropathic deficits. This review focuses on the relationship of alpha-lipoic acid and auto-oxidative glycosylation. It discusses the impact of alpha-lipoic acid on hyperglycemia-induced oxidative stress, and examines the role of alpha-lipoic acid in preventing glycation process and nerve hypoxia."


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"Alpha-Lipoic Acid and Diabetic Neuropathy Vallianou N, Evangelopoulos A, Koutalas P. Alpha-Lipoic Acid and Diabetic Neuropathy. The Review of Diabetic Studies : RDS. 2009;6(4):230-236. doi:10.1900/RDS.2009.6.230. Diabetic neuropathy presents a major public health problem. It is defined by the symptoms and signs of peripheral nerve dysfunction in diabetic patients, in whom other causes of neuropathy have been excluded. Pathogenetic mechanisms that have been implicated in diabetic neuropathy are: a) increased flux through the polyol pathway, leading to accumulation of sorbitol, a reduction in myo-inositol, and an associated reduced Na+-K+-ATPase activity, and b) endoneurial microvascular damage and hypoxia due to nitric oxide inactivation by increased oxygen free radical activity. Alpha-lipoic acid seems to delay or reverse peripheral diabetic neuropathy through its multiple antioxidant properties. Treatment with alpha-lipoic acid increases reduced glutathione, an important endogenous antioxidant. In clinical trials, 600 mg alpha-lipoic acid has been shown to improve neuropathic deficits. This review focuses on the relationship of alpha-lipoic acid and auto-oxidative glycosylation. It discusses the impact of alpha-lipoic acid on hyperglycemia-induced oxidative stress, and examines the role of alpha-lipoic acid in preventing glycation process and nerve hypoxia."


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"Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials Ziegler D, Reljanovic M, Mehnert H, Gries FA. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes. 1999;107(7):421-30. Review. PubMed PMID: 10595592. Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycaemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. In the past two decades several medical treatments that exert their effects despite hyperglycaemia have been derived from the experimental pathogenetic concepts of diabetic neuropathy. Such compounds have been designed to improve or slow the progression of the neuropathic process and are being evaluated in clinical trials, but with the exception of alpha-lipoic acid (thioctic acid) which is available in Germany, none of these drugs is currently available in clinical practice. Here we review the current evidence from the clinical trials that assessed the therapeutic efficacy and safety of thioctic acid in diabetic polyneuropathy. Thus far, 15 clinical trials have been completed using different study designs, durations of treatment, doses, sample sizes, and patient populations. Within this variety of clinical trials, those with beneficial effects of thioctic acid on either neuropathic symptoms and deficits due to polyneuropathy or reduced heart rate variability resulting from cardiac autonomic neuropathy used doses of at least 600 mg per day. The following conclusions can be drawn from the recent controlled clinical trials. 1.) Short-term treatment for 3 weeks using 600 mg of thioctic acid i.v. per day appears to reduce the chief symptoms of diabetic polyneuropathy. A 3-week pilot study of 1800 mg per day given orally indicates that the therapeutic effect may be independent of the route of administration, but this needs to be confirmed in a larger sample size. 2.) The effect on symptoms is accompanied by an improvement of neuropathic deficits. 3.) Oral treatment for 4-7 months tends to reduce neuropathic deficits and improves cardiac autonomic neuropathy. 4.) Preliminary data over 2 years indicate possible long-term improvement in motor and sensory nerve conduction in the lower limbs. 5.) Clinical and postmarketing surveillance studies have revealed a highly favourable safety profile of the drug. Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I Study) is being conducted in North America and Europe aimed at slowing the progression of diabetic polyneuropathy using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment."


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"Effects of dietary supplementation of alpha-lipoic acid on early glomerular injury in diabetes mellitus Melhem MF, Craven PA, Derubertis FR. Effects of dietary supplementation of alpha-lipoic acid on early glomerular injury in diabetes mellitus. J Am Soc Nephrol. 2001 Jan;12(1):124-33. PubMed PMID: 11134258. Antioxidants, in particular vitamin E (VE), have been reported to protect against diabetic renal injury. alpha-Lipoic acid (LA) has been found to attenuate diabetic peripheral neuropathy, but its effects on nephropathy have not been examined. In the present study, parameters of glomerular injury were examined in streptozotocin diabetic rats after 2 mo on unsupplemented diets and in diabetic rats that received the lowest daily dose of dietary LA (30 mg/kg body wt), VE (100 IU/kg body wt), or vitamin C (VC; 1 g/kg body wt), which detectably increased the renal cortical content of each antioxidant. Blood glucose values did not differ among the diabetic groups. At 2 mo, inulin clearance, urinary albumin excretion, fractional albumin clearance, glomerular volume, and glomerular content of immunoreactive transforming growth factor-beta (TGF-beta) and collagen alpha1 (IV) all were significantly increased in unsupplemented D compared with age-matched nondiabetic controls. With the exception of inulin clearance, LA prevented or significantly attenuated the increase in all of these glomerular parameters in D, as well as the increases in renal tubular cell TGF-beta seen in D. At the dose used, VE reduced inulin clearance in D to control levels but failed to alter any of the other indices of glomerular injury or to suppress renal tubular cell TGF-beta in D. VC suppressed urinary albumin excretion, fractional albumin clearance, and glomerular volume but not glomerular or tubular TGF-beta or glomerular collagen alpha1 (IV) content. LA but not VE or VC significantly increased renal cortical glutathione content in D. These data indicate that LA is effective in the prevention of early diabetic glomerular injury and suggest that this agent may have advantages over high doses of either VE or VC."


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"Lipoic acid confers protection against oxidative injury in non-neuronal and neuronal tissue Lynch MA. Lipoic acid confers protection against oxidative injury in non-neuronal and neuronal tissue. Nutr Neurosci. 2001;4(6):419-38. Review. PubMed PMID: 11843262. In the past decade or so, a convincing link between oxidative stress and degenerative conditions has been made and with the knowledge that oxidatiye changes may actually trigger deterioration in cell function, a great deal of energy has focussed on identifying agents which may have possible therapeutic value in combating oxidative changes. One agent which has received attention, because of its powerful antioxidative effects, particularly in neuronal tissue, is lipoic acid."


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"In vivo effect of lipoic acid on lipid peroxidation in patients with diabetic neuropathy Androne L, Gavan NA, Veresiu IA, Orasan R. In vivo effect of lipoic acid on lipid peroxidation in patients with diabetic neuropathy. In Vivo. 2000 Mar-Apr;14(2):327-30. PubMed PMID: 10836205. BACKGROUND: The diabetic state, in both humans and experimental animals, is associated with oxidative stress. Lipid peroxidation of nerve membranes has been suggested as a mechanism by which peripheral nerve ischemia and hypoxia could cause neuropathy. Lipoic acid (LA) is a powerful inhibitor of iron-dependent lipid peroxidation and reactive oxygen species. The treatment of diabetic peripheral and cardiac autonomic neuropathy with LA is based on good clinical and experimental evidence. MATERIALS AND METHODS: To investigate the magnitude of the oxidative stress, serum ceruloplasmin (Cp) and lipid peroxide (Lp) levels were measured in 10 patients with diabetic neuropathy, before and 70 days after treatment with single dose of 600 mg LA/day. For other 12 healthy age- and sex-matched control subjects the serum Cp and Lp levels were evaluated. RESULTS: Our results show that hyperglycemia is a factor for an increase in serum ceruloplasmin in patients with diabetic neuropathy compared to healthy subjects (p < 0.0001). High serum ceruloplasmin (Cp) level in patients with diabetes may be related to antioxidant defense. The treatment of diabetic neuropathy with LA does not affect significantly the serum Cp activity. The serum Lp levels after LA administration were significantly lower (p < 0.005) than those before treatment. CONCLUSIONS: The antioxidant therapy with LA improves and may prevent diabetic neuropathy. This improvement is associated with a reduction in the indexes of lipid peroxidation. Oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia autooxidation."


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N-Acetyl Cysteine (NAC)

"N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases Li J, et al. N-acetyl-cysteine attenuates neuropathic pain by suppressing matrix metalloproteinases. Pain. 2016 Aug;157(8):1711-23. doi: 10.1097/j.pain.0000000000000575. PubMed PMID: 27075430. The treatment of neuropathic pain remains a clinical challenge because of its unclear mechanisms and broad clinical morbidity. Matrix metalloproteinase (MMP)-9 and MMP-2 have previously been described as key components in neuropathic pain because of their facilitation of inflammatory cytokine maturation and induction of neural inflammation. Therefore, the inhibition of MMPs may represent a novel therapeutic approach to the treatment of neuropathic pain. In this study, we report that N-acetyl-cysteine (NAC), which is a broadly used respiratory drug, significantly attenuates neuropathic pain through a unique mechanism of MMP inhibition. Both the in vitro (0.1 mM) and in vivo application of NAC significantly suppressed the activity of MMP-9/2. Orally administered NAC (50, 100, and 200 mg/kg) not only postponed the occurrence but also inhibited the maintenance of chronic constrictive injury (CCI)-induced neuropathic pain in rats. The administration of NAC blocked the maturation of interleukin-1β, which is a critical substrate of MMPs, and markedly suppressed the neuronal activation induced by CCI, including inhibiting the phosphorylation of protein kinase Cγ, NMDAR1, and mitogen-activated protein kinases. Finally, NAC significantly inhibited CCI-induced microglia activation but elicited no notable effects on astrocytes. These results demonstrate an effective and safe approach that has been used clinically to alleviate neuropathic pain through the powerful inhibition of the activation of MMPs."


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"N-acetylcysteine inhibits hyperglycemia-induced oxidative stress and apoptosis markers in diabetic neuropathy Kamboj SS, Vasishta RK, Sandhir R. N-acetylcysteine inhibits hyperglycemia-induced oxidative stress and apoptosis markers in diabetic neuropathy. J Neurochem. 2010 Jan;112(1):77-91. doi: 10.1111/j.1471-4159.2009.06435.x. Epub 2009 Oct 15. PubMed PMID: 19840221. Several studies have indicated the involvement of oxidative stress in the development of diabetic neuropathy. In the present study, we have targeted oxidative stress mediated nerve damage in diabetic neuropathy using N-acetyl-l-cysteine (NAC), a potent antioxidant. After 8 weeks, streptozotocin-induced diabetic rats developed neuropathy which was evident from decreased tail-flick latency (thermal hyperalgesia). This was accompanied by decreased motor coordination as assessed by performance on rota-rod treadmill. Na(+) K(+) ATPase, a biochemical marker of development of diabetic neuropathy, was significantly inhibited in sciatic nerve of diabetic animals. NAC treatment at a daily dose between 1.4 and 1.5 g/kg body weight to diabetic animals for 7 weeks in drinking water ameliorated hyperalgesia, improved motor coordination and reversed reduction in Na(+) K(+) ATPase activity. There was an increase in lipid peroxidation in sciatic nerve of diabetic animals along with decrease in phospholipid levels, while NAC treatment attenuated lipid peroxidation and restored phospholipids to control levels. This was associated with decrease in glutathione and protein thiols. The activities of antioxidant enzymes; superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and glutathione-S-transferase were reduced in sciatic nerve of diabetic animals. Cytochrome c release and active caspase 3 were markedly increased in nerve from diabetic animals suggesting activation of apoptotic pathway. NAC treatment significantly ameliorated decrease in antioxidant defense and prevented cytochrome c release and caspase 3 activation. Electron microscopy revealed demyelination, Wallerian degeneration and onion-bulb formation in sciatic nerve of diabetic rats. NAC on the other hand was able to reverse structural deficits observed in sciatic nerve of diabetic rats. Our results clearly demonstrate protective effect of NAC is mediated through attenuation of oxidative stress and apoptosis, and suggest therapeutic potential of NAC in attenuation of diabetic neuropathy."


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"Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine Sagara M, et al. Inhibition of development of peripheral neuropathy in streptozotocin-induced diabetic rats with N-acetylcysteine. Diabetologia. 1996 Mar;39(3):263-9. PubMed PMID: 8721770. N-acetylcysteine (NAC) is a precursor of glutathione (GSH) synthesis, a free radical scavenger and an inhibitor of tumour necrosis factor alpha (TNF). Because these functions might be beneficial in diabetic complications, in this study we examined whether NAC inhibits peripheral neuropathy. Motor nerve conduction velocity (MNCV) was significantly decreased in streptozotocin-induced-diabetic Wistar rats compared to control rats. Oral administration of NAC reduced the decline of MNCV in diabetic rats. Structural analysis of the sural nerve disclosed significant reduction of fibres undergoing myelin wrinkling and inhibition of myelinated fibre atrophy in NAC-treated diabetic rats. NAC treatment had no effect on blood glucose levels or on the nerve glucose, sorbitol and cAMP contents, whereas it corrected the decreased GSH levels in erythrocytes, the increased lipid peroxide levels in plasma and the increased lipopolysaccharide-induced TNF activity in sera of diabetic rats. Thus, NAC inhibited the development of functional and structural abnormalities of the peripheral nerve in streptozotocin-induced diabetic rats."


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"N-acetylcysteine downregulates phosphorylated p-38 expression but does not reverse the increased superoxide anion levels in the spinal cord of rats with neuropathic pain Horst A, et al. N-acetylcysteine downregulates phosphorylated p-38 expression but does not reverse the increased superoxide anion levels in the spinal cord of rats with neuropathic pain. Brazilian Journal of Medical and Biological Research. 2017;50(2):e5801. doi:10.1590/1414-431X20165801. We determined the effect of N-acetylcysteine (NAC) on the expression of the phosphorylated p38 (p-p38) protein and superoxide anion generation (SAG), two important players in the processing of neuropathic pain, in the lumbosacral spinal cord of rats with chronic constriction injury (CCI)-induced neuropathic pain. The sciatic functional index (SFI) was also measured to assess the functional recovery post-nerve lesion. Thirty-six male Wistar rats were divided equally into the following groups: Naive (rats did not undergo surgical manipulation); Sham (rats in which all surgical procedures involved in CCI were used except the ligature), and CCI (rats in which four ligatures were tied loosely around the right common sciatic nerve), which received 2, 4, or 8 intraperitoneal injections of NAC (150 mg·kg-1·day-1) or saline beginning 4 h after CCI. Rats were sacrificed 1, 3, and 7 days after CCI. The SFI was measured on these days and the lumbosacral spinal cord was used for analysis of p-p38 expression and SAG. CCI induced a decrease in SFI as well as an increase in p-p38 expression and SAG in the spinal cord. The SFI showed a partial recovery at day 7 in saline-treated CCI rats, but recovery was improved in NAC-treated CCI rats. NAC induced a downregulation in p-p38 expression at all time-points evaluated, but did not reverse the increased SAG induced by CCI. Since p-p38 is a mediator in neuropathic pain and/or nerve regeneration, modulation of this protein may play a role in NAC-induced effects in CCI rats."


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"N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors Bernabucci M, et al. N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors. Mol Pain. 2012 Oct 23;8:77. doi: 10.1186/1744-8069-8-77. PubMed PMID: 23088864; PubMed Central PMCID: PMC3543227. BACKGROUND: Pharmacological activation of type-2 metabotropic glutamate receptors (mGlu2 receptors) causes analgesia in experimental models of inflammatory and neuropathic pain. Presynaptic mGlu2 receptors are activated by the glutamate released from astrocytes by means of the cystine/glutamate antiporter (System x(c)(-) or Sx(c)(-)). We examined the analgesic activity of the Sx(c)(-) activator, N-acetyl-cysteine (NAC), in mice developing inflammatory or neuropathic pain. RESULTS: A single injection of NAC (100 mg/kg, i.p.) reduced nocifensive behavior in the second phase of the formalin test. NAC-induced analgesia was abrogated by the Sxc- inhibitor, sulphasalazine (8 mg/kg, i.p.) or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). NAC still caused analgesia in mGlu3(-/-) mice, but was inactive in mGlu2(-/-) mice. In wild-type mice, NAC retained the analgesic activity in the formalin test when injected daily for 7 days, indicating the lack of tolerance. Both single and repeated injections of NAC also caused analgesia in the complete Freund's adjuvant (CFA) model of chronic inflammatory pain, and, again, analgesia was abolished by LY341495. Data obtained in mice developing neuropathic pain in response to chronic constriction injury (CCI) of the sciatic nerve were divergent. In this model, a single injection of NAC caused analgesia that was reversed by LY341495, whereas repeated injections of NAC were ineffective. Thus, tolerance to NAC-induced analgesia developed in the CCI model, but not in models of inflammatory pain. The CFA and CCI models differed with respect to the expression levels of xCT (the catalytic subunit of Sx(c)(-)) and activator of G-protein signaling type-3 (AGS3) in the dorsal portion of the lumbar spinal cord. CFA-treated mice showed no change in either protein, whereas CCI mice showed an ipislateral reduction in xCT levels and a bilateral increase in AGS3 levels in the spinal cord. CONCLUSIONS: These data demonstrate that pharmacological activation of Sxc- causes analgesia by reinforcing the endogenous activation of mGlu2 receptors. NAC has an excellent profile of safety and tolerability when clinically used as a mucolytic agent or in the management of acetaminophen overdose. Thus, our data encourage the use of NAC for the experimental treatment of inflammatory pain in humans."


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Acetyl l-carnitine

"Acetyl-L-Carnitine in the Treatment of Peripheral Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Li S, et al. Acetyl-L-Carnitine in the Treatment of Peripheral Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cameron DW, ed. PLoS ONE. 2015;10(3):e0119479. doi:10.1371/journal.pone.0119479. Acetyl-L-carnitine (ALC), a constructive molecule in fatty acid metabolism, is an agent potentially effective for treating peripheral neuropathic pain (PNP). Its effect, however, remains uncertain. We aimed to access the efficacy and safety of ALC for the treatment of patients with PNP. The current evidence suggests that ALC has a moderate effect in reducing pain measured on VAS in PNP patients with acceptable safety. Larger trials with longer follow-up, however, are warranted to establish the effects."


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"Acetyl-L-Carnitine in the Treatment of Peripheral Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Li S, et al. Acetyl-L-Carnitine in the Treatment of Peripheral Neuropathic Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cameron DW, ed. PLoS ONE. 2015;10(3):e0119479. doi:10.1371/journal.pone.0119479. Acetyl-L-carnitine (ALC), a constructive molecule in fatty acid metabolism, is an agent potentially effective for treating peripheral neuropathic pain (PNP). Its effect, however, remains uncertain. We aimed to access the efficacy and safety of ALC for the treatment of patients with PNP. The current evidence suggests that ALC has a moderate effect in reducing pain measured on VAS in PNP patients with acceptable safety. Larger trials with longer follow-up, however, are warranted to establish the effects."


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"Acetyl-L-carnitine in neuropathic pain: experimental data Chiechio S, Copani A, Gereau RW 4th, Nicoletti F. Acetyl-L-carnitine in neuropathic pain: experimental data. CNS Drugs. 2007;21 Suppl 1:31-8; discussion 45-6. Review. PubMed PMID: 17696591. Acetyl-L-carnitine (ALC) has gained clinical interest for its analgesic effect in different forms of neuropathies associated with chronic pain, such as diabetic and HIV-related peripheral neuropathies. The antinociceptive effect of ALC has been confirmed in several experimental models of neuropathic pain, including streptozotocin- and chemotherapy-induced neuropathy, and the sciatic nerve chronic constriction injury model. In these models, prophylactic administration of ALC has proven to be effective in preventing the development of neuropathic pain. In addition, ALC is known to produce a strong antinociceptive effect when given after neuropathic pain has been established. ALC can also improve the function of peripheral nerves by increasing nerve conduction velocity, reducing sensory neuronal loss, and promoting nerve regeneration. Analgesia requires repeated administrations of ALC, suggesting that the drug regulates neuroplasticity across the pain neuraxis. Recent evidence indicates that ALC regulates processes that go beyond its classical role in energy metabolism. These processes involve the activation of muscarinic cholinergic receptors in the forebrain, and an increased expression of type-2 metabotropic glutamate (mGlu2) receptors in dorsal root ganglia neurons. Induction of mGlu2 receptors is mediated by acetylation mechanisms that involve transcription factors of the nuclear factor (NF)-kappaB family."


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"Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials Sima AA, Calvani M, Mehra M, Amato A; Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005 Jan;28(1):89-94. PubMed PMID: 15616239. OBJECTIVE: We evaluated frozen databases from two 52-week randomized placebo-controlled clinical diabetic neuropathy trials testing two doses of acetyl-L-carnitine (ALC): 500 and 1,000 mg/day t.i.d. RESEARCH DESIGN AND METHODS: Intention-to-treat patients amounted to 1,257 or 93% of enrolled patients. Efficacy end points were sural nerve morphometry, nerve conduction velocities, vibration perception thresholds, clinical symptom scores, and a visual analogue scale for most bothersome symptom, most notably pain. The two studies were evaluated separately and combined. RESULTS: Data showed significant improvements in sural nerve fiber numbers and regenerating nerve fiber clusters. Nerve conduction velocities and amplitudes did not improve, whereas vibration perception improved in both studies. Pain as the most bothersome symptom showed significant improvement in one study and in the combined cohort taking 1,000 mg ALC. CONCLUSIONS: These studies demonstrate that ALC treatment is efficacious in alleviating symptoms, particularly pain, and improves nerve fiber regeneration and vibration perception in patients with established diabetic neuropathy."


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"Acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy: a short review De Grandis D. Acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy: a short review. CNS Drugs. 2007;21 Suppl 1:39-43; discussion 45-6. Review. PubMed PMID: 17696592. Peripheral neurotoxicity is a major complication associated with the use of chemotherapeutic agents such as platinum compounds, taxanes and vinca alkaloids. The neurotoxicity of chemotherapy depends not only on the anticancer agent(s) used, the cumulative dose and the delivery method, but also on the capacity of the nerve to cope with the nerve-damaging process. The sensory and motor symptoms and signs of neurotoxicity are disabling, and have a significant impact on the quality of life of cancer patients. Moreover, the risk of cumulative toxicity may limit the use of highly effective chemotherapeutic agents. Therefore, prophylaxis and treatment of peripheral neurotoxicity secondary to chemotherapy are major clinical issues. Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, plays an essential role in intermediary metabolism. Some of the properties exhibited by ALC include neuroprotective and neurotrophic actions, antioxidant activity, positive actions on mitochondrial metabolism, and stabilisation of intracellular membranes. ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various aetiologies, including chemotherapy-induced peripheral neuropathy (CIPN). In several experimental settings, the prophylactic administration of ALC prevented the occurrence of peripheral neurotoxicity commonly induced by chemotherapeutic agents. In animal models of CIPN, ALC administration promoted the recovery of nerve conduction velocity, restored the mechanical nociceptive threshold, and induced analgesia by up-regulating the expression of type-2 metabotropic glutamate receptors in dorsal root ganglia. These results, plus the favourable safety profile of ALC in neuropathies of other aetiologies, have led to the effects of ALC on CIPN being investigated in cancer patients. Preliminary results have confirmed the reasonably good tolerability profile and the efficacy of ALC on CIPN. The present studies support the use of ALC in cancer patients with persisting neurotoxicity induced by paclitaxel or cisplatin treatment."


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"Acetyl-L-carnitine in diabetic polyneuropathy: experimental and clinical data Sima AA. Acetyl-L-carnitine in diabetic polyneuropathy: experimental and clinical data. CNS Drugs. 2007;21 Suppl 1:13-23; discussion 45-6. Review. PubMed PMID: 17696589. Diabetic polyneuropathy (DPN) is the most common late complication of diabetes mellitus. The underlying pathogenesis is multifaceted, with partly interrelated mechanisms that display a dynamic course. The mechanisms underlying DPN in type 1 and type 2 diabetes mellitus show overlaps or may differ. The differences are mainly due to insulin deficiency in type 1 diabetes which exacerbates the abnormalities caused by hyperglycaemia. Experimental DPN in rat models have identified early metabolic abnormalities with consequences for nerve conduction velocities and endoneurial blood flow. When corrected, the early functional deficits are usually normalised. On the other hand, if not corrected, they lead to abnormalities in lipid peroxidation and expression of neurotrophic factors which in turn result in axonal, nodal and paranodal degenerative changes with worsening of nerve function. As the structural changes progress, they become increasingly less amendable to metabolic interventions. In the past several years, experimental drugs--such as aldose reductase inhibitors, antioxidants and protein kinase C inhibitors--have undergone clinical trials, with disappointing outcomes. These drugs, targeting a single underlying pathogenetic factor, have in most cases been initiated at the advanced stage of DPN. In contrast, substitution of acetyl-L-carnitine (ALC) or C-peptide in type 1 DPN target a multitude of underlying mechanisms and are therefore more likely to be effective on a broader spectrum of the underlying pathogenesis. Clinical trials utilising ALC have shown beneficial effects on nerve conduction slowing, neuropathic pain, axonal degenerative changes and nerve fibre regeneration, despite relatively late initiation in the natural history of DPN. Owing to the good safety profile of ALC, early initiation of ALC therapy would be justified, with potentially greater benefits."


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L-Arginine

"Prophylactic L-arginine and ibuprofen delay the development of tactile allodynia and suppress spinal miR-155 in a rat model of diabetic neuropathy El-Lithy GM, et al. Prophylactic L-arginine and ibuprofen delay the development of tactile allodynia and suppress spinal miR-155 in a rat model of diabetic neuropathy. Transl Res. 2016 Nov;177:85-97.e1. doi: 10.1016/j.trsl.2016.06.005. Epub 2016 Jun 23. PubMed PMID: 27392937. Diabetic neuropathy (DN) is a common complication of diabetes mellitus that is hardly reversible at the late stages. Since treatment of neuropathic pain is predominantly symptomatic, a prophylactic measure would be useful. Both ibuprofen and L-arginine exert antiallodynic effects on chronic constriction injury (CCI)-induced cold allodynia. Furthermore, ibuprofen is effective in CCI-induced mechanical allodynia. The aim of the study was to assess the antiallodynic effect of prophylactic ibuprofen and L-arginine in streptozotocin-induced DN in rats and to further investigate the role of spinal miR-155 and nitric oxide (NO) in this effect. Tactile allodynia was assessed weekly by von Frey filaments. Oral daily administration of ibuprofen, L-arginine and their combination, for 4 weeks starting 1 week after streptozotocin injection (ie, before the development of tactile allodynia), resulted in a significant decrease of tactile allodynia compared with the control diabetic group. This was evident in the fifth week of the experiment. The 3 treatments prevented the decrease in muscle fiber diameter and epidermal thickness, seen in the control diabetic group. Furthermore, ibuprofen, L-arginine and their combination prevented the increase in the spinal NO level and miRNA-155, seen in the control diabetic group. In conclusion, both ibuprofen and L-arginine delayed the development of behavioral and histologic changes of DN, with concomitant suppression of spinal miR-155 and NO level. L-arginine being tolerable may be useful prophylactically in diabetic patients."


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"L-Arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration Rondón LJ, et al. L-Arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration. Eur J Nutr. 2017 Jul 19. doi: 10.1007/s00394-017-1508-x. [Epub ahead of print] PubMed PMID: 28725942. PURPOSE: Neuropathic pain is a common diabetic complication. It is characterized by symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. L-Arginine is a common precursor of many metabolites of biological interest, in particular, nitric oxide (NO), ornithine, and hence polyamines. In central nervous system, NO, glutamate, and polyamines share an N-methyl-D-aspartate (NMDA) receptor-mediated effect. We hypothesized that a variation in arginine metabolism caused by diabetes may contribute to development and maintenance of neuropathic pain and to the worsening of clinical and biological signs of diabetes. METHODS: We examined whether oral L-arginine supplementation (2.58 ± 0.13 g/l in drinking water for 3 weeks) could improve the development of neuropathic pain and the clinical, biological, and metabolic complications of diabetes in streptozocin (STZ)-induced diabetic (D) rats. RESULTS: STZ administration induced classical symptoms of type 1 diabetes. Diabetic rats also displayed mechanical hypersensitivity, tactile, and thermal allodynia. Plasma citrulline and NO levels were increased in diabetic hyperalgesic/allodynic rats. L-Arginine supplementation failed to reduce hyperglycaemia, polyphagia, and weight loss. Moreover, it abolished hyperalgesia and allodynia by normalizing NO plasma concentration and increasing plasma agmatine concentration. CONCLUSIONS: L-Arginine supplementation prevented the development of mechanical hyperalgesia, tactile, and thermal allodynia in painful diabetic neuropathy with concomitant reduction of NO and increased agmatine production, offering new therapeutic opportunities for the management of diabetic neuropathic pain. "


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Moringa Oleifera

"Bioactive Extract from Moringa oleifera Inhibits the Pro-inflammatory Mediators in Lipopolysaccharide Stimulated Macrophages Fard MT, Arulselvan P, Karthivashan G, Adam SK, Fakurazi S. Bioactive Extract from Moringa oleifera Inhibits the Pro-inflammatory Mediators in Lipopolysaccharide Stimulated Macrophages. Pharmacognosy Magazine. 2015;11(Suppl 4):S556-S563. doi:10.4103/0973-1296.172961. Introduction: Inflammation is a well-known physiological response to protect the body against infection and restore tissue injury. Nevertheless, the chronic inflammation can trigger various inflammatory associated diseases/disorder. Moringa oleifera is a widely grown plant in most tropical countries and it has been recognized traditionally for several medicinal benefits. Objectives: The objective of this study was to investigate the anti-inflammatory properties of M. oleifera extract on lipopolysaccharide (LPS) - stimulated macrophages. Materials and Methods: The anti-inflammatory effect of M. oleifera hydroethanolic bioactive leaves extracts was evaluated by assessing the inhibition of nitric oxide (NO) production during Griess reaction and the expression of pro-inflammatory mediators in macrophages. Results: Interestingly, we found that M. oleifera hydroethanolic bioactive leaves extract significantly inhibited the secretion of NO production and other inflammatory markers such as prostaglandin E2, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1β. Meanwhile, the bioactive extract has induced the production of IL-10 in a dose-dependent manner. In addition, M. oleifera hydroethanolic bioactive leaves extract effectively suppressed the protein expression of inflammatory markers inducible NO synthase, cyclooxygenase-2, and nuclear factor kappa-light-chain-enhancer of activated B-cells p65 in LPS-induced RAW264.7 macrophages in a dose-dependent manner. Conclusion: These findings support the traditional use of M. oleifera plant as an effective treatment for inflammation associated diseases/disorders."


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"The Antidiabetic Effect of Low Doses of Moringa oleifera Lam. Seeds on Streptozotocin Induced Diabetes and Diabetic Nephropathy in Male Rats Al-Malki AL, El Rabey HA. The Antidiabetic Effect of Low Doses of Moringa oleifera Lam. Seeds on Streptozotocin Induced Diabetes and Diabetic Nephropathy in Male Rats. BioMed Research International. 2015;2015:381040. doi:10.1155/2015/381040. The antidiabetic activity of two low doses of Moringa seed powder (50 and 100 mg/kg body weight, in the diet) on streptozotocin (STZ) induced diabetes male rats was investigated. Forty rats were divided into four groups. The diabetic positive control (STZ treated) group showed increased lipid peroxide, increased IL-6, and decreased antioxidant enzyme in the serum and kidney tissue homogenate compared with that of the negative control group. Immunoglobulins (IgA, IgG), fasting blood sugar, and glycosylated hemoglobin (HbA1c) were also increased as a result of diabetes in G2 rats. Moreover albumin was decreased, and liver enzymes and α-amylase were not affected. In addition, the renal functions and potassium and sodium levels in G2 were increased as a sign of diabetic nephropathy. Urine analysis showed also glucosuria and increased potassium, sodium, creatinine, uric acid, and albumin levels. Kidney and pancreas tissues showed also pathological alteration compared to the negative control group. Treating the diabetic rats with 50 or 100 mg Moringa seeds powder/kg body weight in G3 and G4, respectively, ameliorated the levels of all these parameters approaching the negative control values and restored the normal histology of both kidney and pancreas compared with that of the diabetic positive control group."


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"Moringa oleifera, a species with potential analgesic and anti-inflammatory activities Martínez-González CL, et al. Moringa oleifera, a species with potential analgesic and anti-inflammatory activities. Biomed Pharmacother. 2017 Mar;87:482-488. doi: 10.1016/j.biopha.2016.12.107. Epub 2017 Jan 7. PubMed PMID: 28073097. Moringa oleifera has long been used in large demand in folk medicine to treat pain. The present study was undertaken to examine the antinociceptive and anti-inflammatory spectrum of M. oleifera leaf extracts discriminating the constituents' nature by using different kind of experimental models in rats. Pharmacological evaluation of a non-polar and/or polar extracts at several doses (30-300mg/kg, p.o.) was explored through experimental nociception using formalin test, carrageenan-induced paw edema and arthritis with subcutaneous injection of collagen in rats. Basic morphology characterization was done by scanning electronic microscopy and laser scanning confocal microscopy. Not only polar (from 30 or 100mg/kg, p.o.) but also non-polar extract produced significant inhibition of the nociceptive behavior with major efficacy in the inflammatory response in different assessed experimental models. This antinociceptive activity involved constituents of different nature and depended on the intensity of the induced painful stimulus. Phytochemical analysis showed the presence of kaempferol-3-glucoside in the polar extract and fatty acids like chlorogenic acid, among others, in the non-polar extract. Data obtained with M. oleifera leaf extracts give evidence of its potential for pain treatment."


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"Biochemical characterization and anti-inflammatory properties of an isothiocyanate-enriched moringa (Moringa oleifera) seed extract Jaja-Chimedza A, et al. Biochemical characterization and anti-inflammatory properties of an isothiocyanate-enriched moringa (Moringa oleifera) seed extract. PLoS One. 2017 Aug 8;12(8):e0182658. doi: 10.1371/journal.pone.0182658. eCollection 2017. PubMed PMID: 28792522; PubMed Central PMCID: PMC5549737. Moringa oleifera Lam. is a tropical plant, used for centuries as food and traditional medicine. The aim of this study was to develop, validate and biochemically characterize an isothiocyanate-enriched moringa seed extract (MSE), and to compare the anti-inflammatory effects of MSE-containing moringa isothiocyanate-1 (MIC-1) with a curcuminoid-enriched turmeric extract (CTE), and a material further enriched in its primary phytochemical, curcumin (curcumin-enriched material; CEM). MSE was prepared by incubating ground moringa seeds with water to allow myrosinase-catalyzed enzymatic formation of bioactive MIC-1, the predominant isothiocyanate in moringa seeds. Optimization of the extraction process yielded an extract of 38.9% MIC-1. Phytochemical analysis of MSE revealed the presence of acetylated isothiocyanates, phenolic glycosides unique to moringa, flavonoids, fats and fatty acids, proteins and carbohydrates. MSE showed a reduction in the carrageenan-induced rat paw edema (33% at 500 mg/kg MIC-1) comparable to aspirin (27% at 300 mg/kg), whereas CTE did not have any significant effect. In vitro, MIC-1 at 1 μM significantly reduced the production of nitric oxide (NO) and at 5 μM, the gene expression of LPS-inducible nitric oxide synthase (iNOS) and interleukins 1β and 6 (IL-1β and IL-6), whereas CEM did not show any significant activity at all concentrations tested. MIC-1 (10μM) was also more effective at upregulating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) target genes NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase pi 1 (GSTP1), and heme oxygenase 1 (HO1) than the CEM. Thus, in contrast to CTE and CEM, MSE and its major isothiocyanate MIC-1 displayed strong anti-inflammatory and antioxidant properties in vivo and in vitro, making them promising botanical leads for the mitigation of inflammatory-mediated chronic disorders."


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"Purification of a chitin-binding protein from Moringa oleifera seeds with potential to relieve pain and inflammation Pereira ML, et al. Purification of a chitin-binding protein from Moringa oleifera seeds with potential to relieve pain and inflammation. Protein Pept Lett. 2011 Nov;18(11):1078-85. PubMed PMID: 21675945. Moringa oleifera Lam. is a perennial multipurpose tree that has been successfully used in folk medicine to cure several inflammatory processes. The aim of this study was to purify and characterize a chitin-binding protein from Moringa oleifera seeds, named Mo-CBP4, and evaluate its antinociceptive and anti-inflammatory effects in vivo. The protein was purified by affinity chromatography on chitin followed by ion exchange chromatography. Acetic acid-induced abdominal constrictions assay was used for the antinociceptive and anti-inflammatory activity assessments. Mo-CBP4 is a glycoprotein (2.9% neutral carbohydrate) composed of two protein subunits with apparent molecular masses of 28 and 18 kDa (9 kDa in the presence of reducing agent). The intraperitoneal injection of Mo-CBP4 (3.5 and 10 mg/kg) into mice 30 min before acetic acid administration potently and significantly reduced the occurrence of abdominal writhing in a dose dependent manner by 44.7% and 100%, respectively. In addition, the oral administration of the protein (10 mg/kg) resulted in 18% and 52.8% reductions in abdominal writhing when given 30 and 60 min prior to acetic acid administration, respectively. Mo-CBP4, when administered by intraperitoneal route, also caused a significant and dose-dependent inhibition of peritoneal capillary permeability induced by acid acetic and significantly inhibited leukocyte accumulation in the peritoneal cavity. In conclusion, this pioneering study describes that the chitin-binding protein Mo-CBP4, from M. oleifera seeds, exhibits anti-inflammatory and antinociceptive properties and scientifically supports the use of this multipurpose tree in folk medicine."


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Curcumin (Tumeric) BCM 95

"Effect of curcumin on diabetic peripheral neuropathic pain: possible involvement of opioid system Banafshe HR, et al. Effect of curcumin on diabetic peripheral neuropathic pain: possible involvement of opioid system. Eur J Pharmacol. 2014 Jan 15;723:202-6. doi: 10.1016/j.ejphar.2013.11.033. Epub 2013 Dec 4. PubMed PMID: 24315931. Neuropathic pain is one of the most common complications of diabetes mellitus. As efficacy and tolerability of current therapy for neuropathic pain are not ideal, we need to develop the novel drug for better treatment. Curcumin as a natural flavonoid from Curcuma longa has considerable effects on nervous system such as, antidepressant, antinociceptive and neuroprotective effects. The present study was designed to investigate the effect of curcumin on diabetic peripheral neuropathic pain and possible involvement of opioid system. A single dose of 60mg/kg streptozotocin was injected intraperitoneally to induce diabetes in rats. STZ-induced diabetic rats were treated with curcumin (50mg/kg/day) acute and chronically. Thermal hyperalgesia and mechanical allodynia were measured on the days 0, 7, 14 and 21 after diabetes induction as behavioral scores of neuropathic pain. Chronic, but not acute, treatment with curcumin prevents the weight loss and attenuates mechanical allodynia in STZ-induced diabetic rats. Pretreatment with naloxone (1mg/kg) significantly reduced anti-allodynic effect of chronic curcumin in von Frey filament test. Our results suggest that curcumin can be considered as a new therapeutic potential for the treatment of diabetic neuropathic pain and the activation of opioid system may be involved in the antinociceptive effect of curcumin."


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"Curcumin Alleviates Neuropathic Pain by Inhibiting p300/CBP Histone Acetyltransferase Activity-Regulated Expression of BDNF and Cox-2 in a Rat Model Zhu X, et al. Curcumin Alleviates Neuropathic Pain by Inhibiting p300/CBP Histone Acetyltransferase Activity-Regulated Expression of BDNF and Cox-2 in a Rat Model. Ma D, ed. PLoS ONE. 2014;9(3):e91303. doi:10.1371/journal.pone.0091303. The management of neuropathic pain is still a major challenge because of its unresponsiveness to most common treatments. Curcumin has been reported to play an active role in the treatment of various neurological disorders, such as neuropathic pain. Curcumin has long been recognized as a p300/CREB-binding protein (CBP) inhibitor of histone acetyltransferase (HAT) activity. However, this mechanism has never been investigated for the treatment of neuropathic pain with curcumin. The aim of the present study was to investigate the anti-nociceptive role of curcumin in the chronic constriction injury (CCI) rat model of neuropathic pain. Furthermore, with this model we investigated the effect of curcumin on P300/CBP HAT activity-regulated release of the pro-nociceptive molecules, brain-derived neurotrophic factor (BDNF) and cyclooxygenase-2 (Cox-2). Treatment with 40 and 60 mg/kg body weight curcumin for 7 consecutive days significantly attenuated CCI-induced thermal hyperalgesia and mechanical allodynia, whereas 20 mg/kg curcumin showed no significant analgesic effect. Chromatin immunoprecipitation analysis revealed that curcumin dose-dependently reduced the recruitment of p300/CBP and acetyl-Histone H3/acetyl-Histone H4 to the promoter of BDNF and Cox-2 genes. A similar dose-dependent decrease of BDNF and Cox-2 in the spinal cord was also observed after curcumin treatment. These results indicated that curcumin exerted a therapeutic role in neuropathic pain by down-regulating p300/CBP HAT activity-mediated gene expression of BDNF and Cox-2."


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"Effect of curcumin in mice model of vincristine-induced neuropathy Babu A, Prasanth KG, Balaji B. Effect of curcumin in mice model of vincristine-induced neuropathy. Pharm Biol. 2015 Jun;53(6):838-48. doi: 10.3109/13880209.2014.943247. Epub 2014 Nov 28. PubMed PMID: 25429779. CONTEXT: Curcumin exhibits a wide spectrum of biological activities which include neuroprotective, antinociceptive, anti-inflammatory, and antioxidant activity. OBJECTIVE: The present study evaluates the effect of curcumin in vincristine-induced neuropathy in a mice model. MATERIALS AND METHODS: Vincristine sulfate (0.1 mg/kg, i.p. for 10 consecutive days) was administered to mice to induce neuropathy. Pain behavior was assessed at different days, i.e., 0, 7, 10, and 14 d. Sciatic nerve total calcium, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), nitric oxide (NO), and lipid peroxidation (LPO) were also estimated after the 14th day of study. Pregabalin (10 mg/kg, p.o.) and curcumin (15, 30, and 60 mg/kg, p.o.) were administered for 14 consecutive days. RESULTS: Curcumin at 60 mg/kg significantly attenuated the vincristine-induced neuropathic pain manifestations in terms of thermal hyperalgesia (p < 0.001) and allodynia (p < 0.001); mechanical hyperalgesia (p < 0.001); functional loss (p < 0.001); and in the delayed phase of formalin test (p < 0.001). Curcumin at 30 and 60 mg/kg exhibited significant changes (p < 0.001) in antioxidant levels and in total calcium levels in vincristine-injected mice. CONCLUSION: Curcumin at 30 and 60 mg/kg dose levels significantly attenuated vincristine-induced neuropathy which may be due to its multiple actions including antinociceptive, calcium inhibitory, and antioxidant effect."


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"Neuroprotective effects of curcumin Cole GM, Teter B, Frautschy SA. Neuroprotective effects of curcumin. Adv Exp Med Biol. 2007;595:197-212. Review. PubMed PMID: 17569212; PubMed Central PMCID: PMC2527619. Neurodegenerative diseases result in the loss of functional neurons and synapses. Although future stem cell therapies offer some hope, current treatments for most of these diseases are less than adequate and ourbest hope is to prevent these devastating diseases. Neuroprotective approaches work best prior to the initiation of damage, suggesting that some safe and effective prophylaxis would be highly desirable. Curcumin has an outstanding safety profile and a number of pleiotropic actions with potential for neuroprotective efficacy, including anti-inflammatory, antioxidant, and anti-protein-aggregate activities. These can be achieved at submicromolar levels. Curcumin's dose-response curves are strongly dose dependent and often biphasic so that in vitro data need to be cautiously interpreted; many effects might not be achievable in target tissues in vivo with oral dosing. However, despite concerns about poor oral bioavailability, curcumin has at least 10 known neuroprotective actions and many of these might be realized in vivo. Indeed, accumulating cell culture and animal model data show that dietary curcumin is a strong candidate for use in the prevention or treatment of major disabling age-related neurodegenerative diseases like Alzheimer's, Parkinson's, and stroke. Promising results have already led to ongoing pilot clinical trials."


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"Curcumin Attenuates Diabetic Neuropathic Pain by Downregulating TNF-α in a Rat Model Li Y, et al. Curcumin Attenuates Diabetic Neuropathic Pain by Downregulating TNF-α in a Rat Model. International Journal of Medical Sciences. 2013;10(4):377-381. doi:10.7150/ijms.5224. The mechanisms involved in diabetic neuropathic pain are complex and involve peripheral and central pathophysiological phenomena. Proinflammatory tumour necrosis factor α (TNF-α) and TNF-α receptor 1, which are markers of inflammation, contribute to neuropathic pain. The purpose of this experimental study was to evaluate the effect of curcumin on diabetic pain in rats. We tested 24 rats with diabetes induced by a single intraperitoneal injection of streptozotocin and 24 healthy control rats. Twelve rats in each group received 60 mg/kg oral curcumin daily for 28 days, and the other 12 received vehicle. On days 7, 14, 21, and 28, we tested mechanical allodynia with von Frey hairs and thermal hyperalgesia with radiant heat. Markers of inflammation in the spinal cord dorsal horn on day 28 were estimated with a commercial assay and Western blot analysis. Compared to control rats, diabetic rats exhibited increased mean plasma glucose concentration, decreased mean body weight, and significant pain hypersensitivity, as evidenced by decreased paw withdrawal threshold to von Frey hairs and decreased paw withdrawal latency to heat. Curcumin significantly attenuated the diabetes-induced allodynia and hyperalgesia and reduced the expression of both TNF-α and TNF-α receptor 1. Curcumin seems to relieve diabetic hyperalgesia, possibly through an inhibitory action on TNF-α and TNF-α receptor 1."


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"Curcumin Could Prevent the Development of Chronic Neuropathic Pain in Rats with Peripheral Nerve Injury Jeon Y, et al. Curcumin Could Prevent the Development of Chronic Neuropathic Pain in Rats with Peripheral Nerve Injury. Current Therapeutic Research, Clinical and Experimental. 2013;74:1-4. doi:10.1016/j.curtheres.2012.10.001. Background: Peripheral nerve injury results in chronic neuropathic pain characterized by allodynia and/or spontaneous pain. It has been suggested that activation of mitogen-activated protein kinases such as extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) contribute to the neuropathic pain. Objectives: We investigated if curcumin could prevent the development of neuropathic pain in rats with chronic constriction injury (CCI) of the sciatic nerve. Methods: The animals were divided into 3 groups. In the curcumin treatment group (n = 10), curcumin (50 mg/kg/d PO) was administered once daily from 1 day before CCI to 7 days after CCI. The rats in the sham group (n = 10) and CCI group (n = 10) received a control vehicle. The mechanical allodynia was assessed using von Frey at 1, 3, 5, and 7 days after nerve injury. Western blots were used to evaluate the levels of p-ERK, p-JNK, and phosphorylation of NR1 (p-NR1) subunits of N-methyl-D-aspartate in the spinal dorsal root ganglion. Results: In the CCI group, mechanical allodynia was observed during 7 days after nerve injury. However, curcumin treatment reversed the mechanical allodynia 7 days after nerve ligation. There were no differences in the expression of p-ERK, p-JNK, and p-NR1 between the sham and curcumin groups. However, the expression of p-ERK, p-JNK, and p-NR1 in the CCI group were higher than the sham group and curcumin group, respectively (P < 0.05). Conclusions: Treatment with curcumin during the early stages of peripheral neuropathy can prevent the development of chronic neuropathic pain."


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Vitamin B1 (benfotiamine)

"The effect of benfotiamine on mu-opioid receptor mediated antinociception in experimental diabetes Nacitarhan C, Minareci E, Sadan G. The effect of benfotiamine on mu-opioid receptor mediated antinociception in experimental diabetes. Exp Clin Endocrinol Diabetes. 2014 Mar;122(3):173-8. doi: 10.1055/s-0033-1363977. Epub 2014 Mar 18. PubMed PMID: 24643695. Diabetic neuropathy is a prevalent, disabling disorder. Currently, the only treatments available to patients with diabetic neuropathy are glucose control and pain management. B vitamin present neuroprotective effects, which are suggested to be related to their analgesic action in various models of neuropathic pain. According to our literature knowledge there is no report about antinociceptive effects of thiamine as benfotiamine and opioids together in diabetic mice. The purpose of this study was to determine the effects of benfotiamine on the antinociception produced by mu-opioid receptor agonist fentanyl in diabetic mice. The effects of benfotiamine on antinociception produced by fentanyl in diabetic mice were studied in 4 groups. Antinociceptive effect was determined with tail flick, hot plate and formalin test. Our results showed that, mu-opioid agonist fentanyl in benfotiamine applied diabetic group caused more potent antinociceptive effect than in diabetic group without benfotiamine treatment. In brief benfotiamine supplement in diet did not bring out antinociceptive effect itself, but during development of STZ diabetes, benfotiamine replacement increased the antinociceptive effect of fentanyl in mice tail-flick test. This effect is probably due to the replacement of benfotiamine efficiency occurring in diabetes mellitus. Finally, we suppose that oral benfotiamine replacement therapy may be useful to ameliorate analgesic effect of mu-opioid agonists on neuropathic pain in diabetic case."


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"Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study) Haupt E, Ledermann H, Köpcke W. Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study). Int J Clin Pharmacol Ther. 2005 Feb;43(2):71-7. Erratum in: Int J Clin Pharmacol Ther. 2005 Jun;43(6):304. PubMed PMID: 15726875. OBJECTIVE: The aim of the study was to evaluate the efficacy of benfotiamine administered over three weeks (allithiamine; a lipid-soluble vitamin B1 prodrug with high bioavailability) to patients with diabetic polyneuropathy in a randomized, placebo-controlled, double-blind, two-center pilot study. MATERIAL AND METHODS: Forty inpatients (23 male, 18 female, age range 18 - 70 years) with a history of type 1 or 2 diabetes and polyneuropathy of not longer than two years, were included in the study. Twenty Patients received two 50 mg benfotiamine tablets four times daily and 20 patients received placebo over the three-week study period. Two clinical units were involved with 10 patients receiving placebo and 10 patients benfotiamine in each. The neuropathy score according to Katzenwadel et al. [1987] was used to evaluate symptoms of polyneuropathy, vibration perception threshold and both the physician's and the patient's own assessment were documented. RESULTS: A statistically significant (p = 0.0287) improvement in the neuropathy score was observed in the group given active drug when compared to the placebo-treated controls. There was no statistically significant change observed in the tuning fork test. The most pronounced effect on complaints was a decrease in pain (p = 0.0414). More patients in the benfotiamine-treated group than in the placebo group considered their clinical condition to have improved (p = 0.052). No side effects attributable to benfotiamine were observed. The differences between the groups cannot be attributed to a change in metabolic parameters since there were no significant alterations in the HbA1 levels and blood sugar profiles. The body mass index of the two groups did not differ. CONCLUSION: This pilot investigation (BEDIP Study) has confirmed the results of two earlier randomized controlled trials and has provided further evidence for the beneficial effects of benfotiamine in patients with diabetic neuropathy."


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"A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6. PubMed PMID: 8886748. In a double-blind, randomized, controlled study, the effectiveness of treatment with a combination of Benfotiamine (an Allithiamine, a lipid-soluble derivative of vitamin B1 with high bioavailability) plus vitamin B6/B12 on objective parameters of neuropathy was studied over a period of 12 weeks on 24 diabetic patients with diabetic polyneuropathy. The results showed a significant improvement (p = 0.006) of nerve conduction velocity in the peroneal nerve and a statistical trend toward improvement of the vibration perception threshold. Long-term observation of 9 patients with verum over a period of 9 months support the results. Therapy-specific adverse effects were not seen. The results of this double-blind investigation, of the long-term observation and of the reports in the literature support the contention that the neurotropic benfotiamine-vitamin B combination represents a starting point in the treatment of diabetic polyneuropathy."


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"Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy Winkler G, et al. Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Arzneimittelforschung. 1999 Mar;49(3):220-4. PubMed PMID: 10219465. The therapeutic effectiveness of a benfotiamine (CAS 22457-89-2)-vitamin B combination (Milgamma-N), administered in high (4 x 2 capsules/day, = 320 mg benfotiamine/day) and medium doses (3 x 1 capsules/day), was compared to a monotherapy with benfotiamine (Benfogamma) (3 x 1 tablets/day, = 150 mg benfotiamine/day) in diabetic patients suffering from painful peripheral diabetic neuropathy (DNP). In a 6-week open clinical trial, 36 patients (aged 40 to 70 yrs) having acceptable metabolic control (HbA1c < 8.0%) were randomly assigned to three groups, each of them comprising 12 participants. Neuropathy was assessed by five parameters: the pain sensation (evaluated by a modified analogue visual scale), the vibration sensation (measured with a tuning fork using the Riedel-Seyfert method) and the current perception threshold (CPT) on the peroneal nerve at 3 frequencies: 5, 250 and 2000 Hz). Parameters were registered at the beginning of the study and at the end of the 3rd and 6th week of therapy. An overall bneneficial therapeutic effect on the neuropathy status was observed in all three groups during the study, and a significant improvement in most of the parameters studied appeared already at the 3rd week of therapy (p < 0.01). The greatest change occurred in the group of patients receiving the high dose of benfotiamine (p < 0.01 and 0.05, resp., compared to the othr groups). Metabolic control did not change over the study. It is concluded that benfotiamine is most effective in large doses, although even in smaller daily dosages, either in combination or in monotherapy, it is effective."


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Vitamin B2 Riboflavin

"Update on riboflavin and multiple sclerosis: a systematic review Naghashpour M, Jafarirad S, Amani R, Sarkaki A, Saedisomeolia A. Update on riboflavin and multiple sclerosis: a systematic review. Iran J Basic Med Sci. 2017 Sep;20(9):958-966. doi: 10.22038/IJBMS.2017.9257. Review. PubMed PMID: 29085589; PubMed Central PMCID: PMC5651462. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Riboflavin plays an important role in myelin formation, and its deficiency is implicated as a risk factor for multiple sclerosis. Here, we systematically reviewed the literature concerning the health benefits of riboflavin on MS. The literature recorded within four main databases, including relevant clinical trials, experimental, and case-control studies from 1976 to 2017 were considered. Both human and animal studies were included for review, with no restrictions on age, gender, or ethnicity. Experimental studies demonstrated that riboflavin deficiency triggers neurologic abnormalities related to peripheral neuropathies such as demyelinating neuropathy. Moreover, randomized controlled trials (RCT) and case-control studies in which MS patients received riboflavin supplementation or had higher dietary riboflavin intake showed improvements in neurological motor disability. Riboflavin is a cofactor of xanthine oxidase and its deficiency exacerbates low uric acid caused by high copper levels, leading to myelin degeneration. The vitamin additionally plays a significant role in the normal functioning of glutathione reductase (GR) as an antioxidant enzyme, and conditions of riboflavin deficiency lead to oxidative damage. Riboflavin promotes the gene and protein levels of brain-derived neurotrophic factor (BDNF) in the CNS of an animal model of MS, suggesting that BDNF mediates the beneficial effect of riboflavin on neurological motor disability. Research to date generally supports the role of riboflavin in MS outcomes. However, further observational and interventional studies on human populations are warranted to validate the effects of riboflavin."


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"Peripheral neuropathy of dietary riboflavin deficiency in chickens Jortner BS, Cherry J, Lidsky TI, Manetto C, Shell L. Peripheral neuropathy of dietary riboflavin deficiency in chickens. J Neuropathol Exp Neurol. 1987;46:544–555. A strain of rapidly growing meat-type chickens was fed a diet deficient in riboflavin from 1–40 days of age. Diminished growth rate, progressive gait abnormality and reluctance to move were noted beginning on day 8. Neurologic abnormalities were related to peripheral neuropathy characterized by Schwann cell hypertrophy and degeneration with cytoplasmic lipid droplets' and segmental demyelination. Lesions were initially detected on day 10, and in concert with clinical signs became more profound between days 14 and 21. Sequestration of myelin debris within Schwann cells was common. Other features of the neuropathy included the presence of endoneurial edema and axonal degeneration involving small numbers of fibers. Remyelination of peripheral nerve fibers in birds on the deficient diet was occasionally seen on day 10, became progressively more prominent, and was marked by day 37. There was an associated, variable but incomplete, clinical improvement evident in later stages of the study. Liver concentrations of riboflavin in deficient birds were significantly reduced on day 13 but not on day 26. This neuropathy may be related to diminished tissue levels of the riboflavin-based coenzymes flavin-adenine dinucleotide (FAD) and flavin mononucleotide (FMN) leading to reduced cellular energy levels and profoundly affecting Schwann cells at some critical point in growth."


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"Peripheral neuropathy of dietary riboflavin deficiency in racing pigeons Wada Y, Kondo H, Itakura C. Peripheral neuropathy of dietary riboflavin deficiency in racing pigeons. J Vet Med Sci. 1996 Feb;58(2):161-3. PubMed PMID: 8672588. An occurrence of peripheral neuropathy in nine 14- to 55-day-old racing pigeons was documented. The predominant clinical signs were diarrhea, and leg and wing paralysis. Grossly, there was discoloration and swelling of all the peripheral nerve trunks. Microscopic lesions comprising swelling, fragmentation and demyelination of myelin sheaths, and proliferation of Schwann cells, were seen in the peripheral nerves of all birds examined. These changes were associated with moderate to severe swelling, fragmentation, atrophy and loss of axons. The peripheral nerve lesions in these cases were similar to those of dietary riboflavin deficiency in chickens. An analysis of the diet given to the pigeons indicated that the riboflavin concentration was only 0.9 mg/kg feed."


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"Severe sensory neuropathy in patients with adult-onset multiple acyl-CoA dehydrogenase deficiency Wang Z, et al. Severe sensory neuropathy in patients with adult-onset multiple acyl-CoA dehydrogenase deficiency. Neuromuscul Disord. 2016 Feb;26(2):170-5. doi: 10.1016/j.nmd.2015.12.002. Epub 2015 Dec 18. PubMed PMID: 26821934. Multiple Acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation. Most patients with late-onset MADD are clinically characterized by lipid storage myopathy with dramatic responsiveness to riboflavin treatment. Abnormalities of peripheral neuropathy have rarely been reported in patients with late-onset MADD. We describe six patients who presented with proximal limb weakness and loss of sensation in the distal limbs. Muscle biopsy revealed typical myopathological patterns of lipid storage myopathy and blood acylcarnitine profiles showed a combined elevation of multiple acylcarnitines supporting the diagnosis of MADD. However, nerve conduction investigations and sural nerve biopsies in these patients indicated severe axonal sensory neuropathy. Causative ETFDH gene mutations were found in all six cases. No other causative gene mutations were identified in mitochondrial DNA and genes associated with hereditary neuropathies through next-generation-sequencing panel. Late-onset patients with ETFDH mutations can present with proximal muscle weakness and distal sensory neuropathy, which might be a new phenotypic variation, but the precise underlying pathogenesis remains to be elucidated."


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Vitamin B6 Pyridoxal-5-Phosphate (P5P)

"Vitamin B6 supplementation can improve peripheral polyneuropathy in patients with chronic renal failure on high‐flux haemodialysis and human recombinant erythropoietin Okada H, et al. Vitamin B6 supplementation can improve peripheral polyneuropathy in patients with chronic renal failure on high‐flux haemodialysis and human recombinant erythropoietin. Nephrology Dialysis Transplantation. 2000 Sep; 15(9). 1410-3. Background. High‐flux haemodialysis (HD) has recently been vigorously promoted as a novel standard, and it can indeed efficiently reduce the occurrence of most uraemic symptoms due to middle molecular toxins and/or underdialysis. However, some symptoms remain problematical, particularly peripheral polyneuropathy (PPN). One of the possible reasons for this is that the patients may have low concentrations of some nutrients, e.g. vitamin B6, necessary for normal peripheral neuron function. Methods. Predialysis serum pyridoxal‐5′‐phosphate (P5P) level was determined in 36 chronic HD patients who were undergoing high‐flux HD and receiving human recombinant erythropoietin. Among them, 26 patients suffered from PPN. Prior to supplementation, these 26 patients were examined and their neurological symptoms were ranked according to our PPN symptom score. Vitamin B6 (60 mg/day) was randomly prescribed to 14 of them, and vitamin B12 (500 μg/day) was prescribed to the others. After 4 weeks, all the patients were re‐examined. Results. We found that predialysis serum P5P levels of HD patients with PPN were not significantly lower than those of matched HD patients without PPN. Nonetheless, it was demonstrated that supplementation with vitamin B6 for 4 weeks significantly increased the predialysis level of P5P and dramatically attenuated PPN symptoms compared with initial symptoms. No improvement was observed in response to vitamin B12 supplementation. Conclusion. This result suggests that although vitamin B6 deficiency could not be demonstrated in patients with chronic renal failure on high‐flux HD, vitamin B6 supplementation was effective in improving PPN symptoms of various aetiologies, possibly because of vitamin B6 resistance to PPN in these patients."


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"Dietary reversal of neuropathy in a murine model of prediabetes and metabolic syndrome Hinder LM, et al. Dietary reversal of neuropathy in a murine model of prediabetes and metabolic syndrome. Dis Model Mech. 2017 Jun 1;10(6):717-725. doi: 10.1242/dmm.028530. Epub 2017 Apr 5. PubMed PMID: 28381495; PubMed Central PMCID: PMC5483005. Patients with metabolic syndrome, which is defined as obesity, dyslipidemia, hypertension and impaired glucose tolerance (IGT), can develop the same macro- and microvascular complications as patients with type 2 diabetes, including peripheral neuropathy. In type 2 diabetes, glycemic control has little effect on the development and progression of peripheral neuropathy, suggesting that other metabolic syndrome components may contribute to the presence of neuropathy. A parallel phenomenon is observed in patients with prediabetes and metabolic syndrome, where improvement in weight and dyslipidemia more closely correlates with restoration of nerve function than improvement in glycemic status. The goal of the current study was to develop a murine model that resembles the human condition. We examined longitudinal parameters of metabolic syndrome and neuropathy development in six mouse strains/genotypes (BKS-wt, BKS-Leprdb/+ , B6-wt, B6-Leprdb/+, BTBR-wt, and BTBR-Lepob/+ ) fed a 54% high-fat diet (HFD; from lard). All mice fed a HFD developed large-fiber neuropathy and IGT. Changes appeared early and consistently in B6-wt mice, and paralleled the onset of neuropathy. At 36 weeks, B6-wt mice displayed all components of the metabolic syndrome, including obesity, IGT, hyperinsulinemia, dyslipidemia and oxidized low density lipoproteins (oxLDLs). Dietary reversal, whereby B6-wt mice fed a HFD from 4-20 weeks of age were switched to standard chow for 4 weeks, completely normalized neuropathy, promoted weight loss, improved insulin sensitivity, and restored LDL cholesterol and oxLDL by 50% compared with levels in HFD control mice. This dietary reversal model provides the basis for mechanistic studies investigating peripheral nerve damage in the setting of metabolic syndrome, and ultimately the development of mechanism-based therapies for neuropathy."


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"Carpal tunnel syndrome and vitamin B6 Ryan-Harshman M, Aldoori W. Carpal tunnel syndrome and vitamin B6. Canadian Family Physician. 2007;53(7):1161-1162. Abstract: QUESTION A 42-year-old woman with carpal tunnel syndrome tells you she has started taking a vitamin B6 supplement to relieve her symptoms. Her work in an automotive parts department involves both lifting moderately heavy packages and typing at a computer terminal. What does the research indicate about vitamin B6 as a treatment option, and what health issues should you discuss with this patient? ANSWER Although its effectiveness is controversial, vitamin B6 is often used as a conservative and adjunct therapy in treatment of carpal tunnel syndrome. Many patients attempt to treat their symptoms with vitamin B6 on their own. Vitamin B6 at less than 200 mg daily is not likely to cause any adverse effects, but patients should be monitored for changes in symptoms, particularly when high doses are taken over long periods."


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"Inflammation causes tissue-specific depletion of vitamin B6 Chiang E-P, et al. Inflammation causes tissue-specific depletion of vitamin B6. Arthritis Research & Therapy. 2005;7(6):R1254-R1262. doi:10.1186/ar1821. Previously we observed strong and consistent associations between vitamin B6 status and several indicators of inflammation in patients with rheumatoid arthritis. Clinical indicators, including the disability score, the length of morning stiffness, and the degree of pain, and biochemical markers, including the erythrocyte sedimentation rate and C-reactive protein levels, were found to be inversely correlated with circulating vitamin B6 levels. Such strong associations imply that impaired vitamin B6 status in these patients results from inflammation. In the present study we examined whether inflammation directly alters vitamin B6 tissue contents and its excretion in vivo. A cross-sectional case-controlled human clinical trial was performed in parallel with experiments in an animal model of inflammation. Plasma and erythrocyte and pyridoxal 5'-phosphate concentrations, urinary 4-pyridoxic acid excretion, and the activity coefficient of erythrocyte aspartate aminotransferase were compared between patients and healthy subjects. Adjuvant arthritis was induced in rats for investigating hepatic and muscle contents as well as the urinary excretion of vitamin B6 during acute and chronic inflammation. Patients with rheumatoid arthritis had low plasma pyridoxal 5'-phosphate compared with healthy control subjects, but normal erythrocyte pyridoxal 5'-phosphate and urinary 4-pyridoxic acid excretion. Adjuvant arthritis in rats did not affect 4-pyridoxic acid excretion or muscle storage of pyridoxal 5'-phosphate, but it resulted in significantly lower pyridoxal 5'-phosphate levels in circulation and in liver during inflammation. Inflammation induced a tissue-specific depletion of vitamin B6. The low plasma pyridoxal 5'-phosphate levels seen in inflammation are unlikely to be due to insufficient intake or excessive vitamin B6 excretion. Possible causes of decreased levels of vitamin B6 are discussed."


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"Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial Fonseca VA, et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med. 2013 Feb;126(2):141-9. doi: 10.1016/j.amjmed.2012.06.022. Epub 2012 Dec 5. PubMed PMID: 23218892. PURPOSE: To determine whether a combination of L-methylfolate, methylcobalamin, and pyridoxal-5'-phosphate (LMF-MC-PLP [Metanx; Pamlab LLC, Covington, La]) improves sensory neuropathy. RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled trial involved 214 patients with type 2 diabetes and neuropathy (baseline vibration perception threshold [VPT]: 25-45 volts), who were randomly assigned to 24 weeks of treatment with either L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg or placebo. The primary end point was effect on VPT. Secondary end points included Neuropathy Total Symptom Score (NTSS-6) and Short Form 36 (SF-36), as well as plasma levels of folate, vitamins B(6) and B(12), methylmalonic acid (MMA), and homocysteine. RESULTS: There was no significant effect on VPT. However, patients receiving LMF-MC-PLP consistently reported symptomatic relief, with clinically significant improvement in NTSS-6 scores at week 16 (P=.013 vs placebo) and week 24 (P=.033). Improvement in NTSS scores was related to baseline MMA and inversely related to baseline PLP and metformin use. Quality-of-life measures also improved. Homocysteine decreased by 2.7±3.0 μmol/L with LMF-MC-PLP versus an increase of 0.5±2.4 μmol/L with placebo (P=.0001). Adverse events were infrequent, with no single event occurring in ≥2% of subjects. CONCLUSIONS: LMF-MC-PLP appears to be a safe and effective therapy for alleviation of peripheral neuropathy symptoms, at least in the short term. Additional long-term studies should be conducted, as the trial duration may have been too short to show an effect on VPT. In addition, further research on the effects in patients with cobalamin deficiency would be useful."


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Vitamin B 9 L-Methylfolate calcium

"Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial Fonseca VA, et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med. 2013 Feb;126(2):141-9. doi: 10.1016/j.amjmed.2012.06.022. Epub 2012 Dec 5. PubMed PMID: 23218892. PURPOSE: To determine whether a combination of L-methylfolate, methylcobalamin, and pyridoxal-5'-phosphate (LMF-MC-PLP [Metanx; Pamlab LLC, Covington, La]) improves sensory neuropathy. RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled trial involved 214 patients with type 2 diabetes and neuropathy (baseline vibration perception threshold [VPT]: 25-45 volts), who were randomly assigned to 24 weeks of treatment with either L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg or placebo. The primary end point was effect on VPT. Secondary end points included Neuropathy Total Symptom Score (NTSS-6) and Short Form 36 (SF-36), as well as plasma levels of folate, vitamins B(6) and B(12), methylmalonic acid (MMA), and homocysteine. RESULTS: There was no significant effect on VPT. However, patients receiving LMF-MC-PLP consistently reported symptomatic relief, with clinically significant improvement in NTSS-6 scores at week 16 (P=.013 vs placebo) and week 24 (P=.033). Improvement in NTSS scores was related to baseline MMA and inversely related to baseline PLP and metformin use. Quality-of-life measures also improved. Homocysteine decreased by 2.7±3.0 μmol/L with LMF-MC-PLP versus an increase of 0.5±2.4 μmol/L with placebo (P=.0001). Adverse events were infrequent, with no single event occurring in ≥2% of subjects. CONCLUSIONS: LMF-MC-PLP appears to be a safe and effective therapy for alleviation of peripheral neuropathy symptoms, at least in the short term. Additional long-term studies should be conducted, as the trial duration may have been too short to show an effect on VPT. In addition, further research on the effects in patients with cobalamin deficiency would be useful."


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"Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate Jacobs AM, Cheng D. Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate. Rev Neurol Dis. 2011;8(1-2):39-47. PubMed PMID: 21769070. Agents used to treat symptoms of diabetic peripheral neuropathy (DPN) are only palliative, not disease modifying. Although studies of monotherapy with L-methylfolate, methylcobalamin, or pyridoxal 5'-phosphate suggest that each of these bioavailable B vitamins may reverse the pathophysiology and symptoms of DPN, data on the efficacy of this combination therapy are limited. Therefore, we assessed the efficacy of an oral combination of L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate for improving epidermal nerve fiber density (ENFD) in the lower extremity of patients with DPN. Eleven consecutive patients with type 2 diabetes with symptomatic DPN were assessed for ENFD at the calf by means of skin punch biopsy and then placed on twice daily oral-combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate. After approximately 6 months of treatment, patients underwent follow-up biopsy. At the end of their treatment, 73% of patients showed an increase in calf ENFD, and 82% of patients experienced both reduced frequency and intensity of paresthesias and/or dysesthesias. This preliminary study suggests that combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate increases ENFD in patients with DPN."


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"Clinicopathologic features of folate-deficiency neuropathy Koike H, et al. Clinicopathologic features of folate-deficiency neuropathy. Neurology. 2015 Mar 10;84(10):1026-33. doi: 10.1212/WNL.0000000000001343. Epub 2015 Feb 6. PubMed PMID: 25663227. OBJECTIVE: The clinical significance and characteristics of neuropathy caused by folate deficiency remain to be established. METHODS: We examined the clinicopathologic features of 18 consecutive patients with neuropathy caused by folate deficiency who presented with low serum folate levels but normal blood thiamine and serum cobalamin levels in the absence of chronic alcoholism. RESULTS: Symptoms were relatively uniform, characterized by slowly progressive polyneuropathy with predominant involvement of the lower extremities, with a tendency to manifest as sensory rather than motor neuropathy and predominant deep rather than superficial sensory loss. The electrophysiologic features were consistent with axonal neuropathy. The histopathologic features of sural nerve biopsy specimens indicated large fiber-predominant axonal loss without segmental demyelination. Although macrocytosis was found in 7 patients, only 3 patients exhibited hemoglobin levels less than 10 g/dL. During the same study period, we found 12 patients who had low blood thiamine levels but normal serum folate and cobalamin levels without chronic alcoholism. Compared with patients who had thiamine-deficiency neuropathy, patients with a folate deficiency showed significantly slower progression (p < 0.01), a tendency to manifest sensory neuropathy (p < 0.05), predominant deep sensory loss (p < 0.01), and preservation of biceps tendon reflexes (p < 0.05). CONCLUSIONS: Folate-deficiency neuropathy was characterized by a slowly progressive and sensory-dominant pattern, which was different from thiamine-deficiency neuropathy (i.e., beriberi neuropathy). This study demonstrates the importance of folate deficiency in the differential diagnosis of neuropathy, particularly in countries where folic acid fortification has not yet been practiced."


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"Uridine monophosphate, folic acid and vitamin B12 in patients with symptomatic peripheral entrapment neuropathies Negrão L, Nunes P; Portuguese Group for the Study of Peripheral Neuropathy. Uridine monophosphate, folic acid and vitamin B12 in patients with symptomatic peripheral entrapment neuropathies. Pain Manag. 2016;6(1):25-9. doi: 10.2217/pmt.15.60. Epub 2015 Dec 17. PubMed PMID: 26679082. BACKGROUND: Carpal tunnel syndrome is the most common type of peripheral entrapment neuropathy. PATIENTS & METHODS: We performed an exploratory, open-label, multicenter, observational study of 48 patients with peripheral entrapment neuropathy. Patients received a daily capsule of uridine monophosphate, folic acid + vitamin B12 for 2 months and were evaluated using the Pain DETECT questionnaire. RESULTS: The global score for pain decreased from 17.3 ± 5.9 at baseline to 10.3 ± 6.1 at the final evaluation (p < 0.001). Concomitant analgesic and anti-inflammatory treatment was stopped or the dose reduced in 77.4% of patients. CONCLUSION: Uridine monophosphate + folic acid + vitamin B12 reduced total pain score, intensity and characterization of pain and associated symptoms. These results should be tested in a well-designed, adequately powered randomized controlled trial."


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"Neuroprotective effects of folic acid on experimental diabetic peripheral neuropathy Yilmaz M, Aktug H, Oltulu F, Erbas O. Neuroprotective effects of folic acid on experimental diabetic peripheral neuropathy. Toxicol Ind Health. 2016 May;32(5):832-40. doi: 10.1177/0748233713511513. Epub 2013 Dec 5. PubMed PMID: 24311627. Diabetic peripheral neuropathy (DPN) is widely considered as a degenerative complication of diabetic patients. The clinical effectiveness of folic acid (FA) on DPN is uncertain. The objective of the present study was to determine the effect of FA in DPN using electromyography (EMG), histopathological examination, immunohistochemistry, inclined plane test, and malondialdehyde (MDA) levels as a marker for lipid peroxidation in experimental diabetic rats. A total of 21 Sprague Dawley rats were randomly divided into 3 groups: control group, diabetes group, and FA-treated group. In EMG, compound muscle action potential (CMAP) amplitude in the sciatic nerve was lower in the diabetes group compared with the control group. CMAP amplitude in the sciatic nerve was higher in the FA-treated group when compared with the diabetes group. Distal latency and CMAP duration in the sciatic nerve were lower in the FA-treated group when compared with the diabetes group. In histopathological examination of the sciatic nerve, peripheral fibrosis was present in the diabetic group; the fibrosis was lower in the FA-treated group. In comparison with the diabetes group, the expression of nerve growth factor (NGF) was higher in the FA-treated group. The scores for the inclined plane test were lower in the diabetes group and higher in the FA-treated group than the control group. The MDA levels were significantly lower in the FA-treated group when compared with the diabetes group.The study suggests that FA can protect diabetic rats against DPN and that the underlying mechanism for this may be related to improvement of the expression of NGF and lower MDA levels."


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Vitamin B12 (as methylcobalamin)

"Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial Fonseca VA, et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med. 2013 Feb;126(2):141-9. doi: 10.1016/j.amjmed.2012.06.022. Epub 2012 Dec 5. PubMed PMID: 23218892. PURPOSE: To determine whether a combination of L-methylfolate, methylcobalamin, and pyridoxal-5'-phosphate (LMF-MC-PLP [Metanx; Pamlab LLC, Covington, La]) improves sensory neuropathy. RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled trial involved 214 patients with type 2 diabetes and neuropathy (baseline vibration perception threshold [VPT]: 25-45 volts), who were randomly assigned to 24 weeks of treatment with either L-methylfolate calcium 3 mg, methylcobalamin 2 mg, and pyridoxal-5'-phosphate 35 mg or placebo. The primary end point was effect on VPT. Secondary end points included Neuropathy Total Symptom Score (NTSS-6) and Short Form 36 (SF-36), as well as plasma levels of folate, vitamins B(6) and B(12), methylmalonic acid (MMA), and homocysteine. RESULTS: There was no significant effect on VPT. However, patients receiving LMF-MC-PLP consistently reported symptomatic relief, with clinically significant improvement in NTSS-6 scores at week 16 (P=.013 vs placebo) and week 24 (P=.033). Improvement in NTSS scores was related to baseline MMA and inversely related to baseline PLP and metformin use. Quality-of-life measures also improved. Homocysteine decreased by 2.7±3.0 μmol/L with LMF-MC-PLP versus an increase of 0.5±2.4 μmol/L with placebo (P=.0001). Adverse events were infrequent, with no single event occurring in ≥2% of subjects. CONCLUSIONS: LMF-MC-PLP appears to be a safe and effective therapy for alleviation of peripheral neuropathy symptoms, at least in the short term. Additional long-term studies should be conducted, as the trial duration may have been too short to show an effect on VPT. In addition, further research on the effects in patients with cobalamin deficiency would be useful."


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"Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials Sun Y, Lai M S, Lu C J. Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials. Acta Neurologica Taiwanica 2005; 14(2): 48-54. This review assessed the effectiveness of vitamin B12 for the treatment of diabetic neuropathy. The authors concluded that vitamin B12 treatment appears to improve symptomatic relief more than electrophysiologic results. This conclusion should be viewed as tentative given the poor quality of the evidence reviewed."


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"Methylcobalamin: A Potential Vitamin of Pain Killer Zhang M, Han W, Hu S, Xu H. Methylcobalamin: A Potential Vitamin of Pain Killer. Neural Plasticity. 2013;2013:424651. doi:10.1155/2013/424651. Methylcobalamin (MeCbl), the activated form of vitamin B12, has been used to treat some nutritional diseases and other diseases in clinic, such as Alzheimer's disease and rheumatoid arthritis. As an auxiliary agent, it exerts neuronal protection by promoting regeneration of injured nerves and antagonizing glutamate-induced neurotoxicity. Recently several lines of evidence demonstrated that MeCbl may have potential analgesic effects in experimental and clinical studies. For example, MeCbl alleviated pain behaviors in diabetic neuropathy, low back pain and neuralgia. MeCbl improved nerve conduction, promoted the regeneration of injured nerves, and inhibited ectopic spontaneous discharges of injured primary sensory neurons. This review aims to summarize the analgesic effect and mechanisms of MeCbl at the present."


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"Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate Jacobs AM, Cheng D. Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate. Rev Neurol Dis. 2011;8(1-2):39-47. PubMed PMID: 21769070. Agents used to treat symptoms of diabetic peripheral neuropathy (DPN) are only palliative, not disease modifying. Although studies of monotherapy with L-methylfolate, methylcobalamin, or pyridoxal 5'-phosphate suggest that each of these bioavailable B vitamins may reverse the pathophysiology and symptoms of DPN, data on the efficacy of this combination therapy are limited. Therefore, we assessed the efficacy of an oral combination of L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate for improving epidermal nerve fiber density (ENFD) in the lower extremity of patients with DPN. Eleven consecutive patients with type 2 diabetes with symptomatic DPN were assessed for ENFD at the calf by means of skin punch biopsy and then placed on twice daily oral-combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate. After approximately 6 months of treatment, patients underwent follow-up biopsy. At the end of their treatment, 73% of patients showed an increase in calf ENFD, and 82% of patients experienced both reduced frequency and intensity of paresthesias and/or dysesthesias. This preliminary study suggests that combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate increases ENFD in patients with DPN."


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"Methylcobalamin effects on diabetic neuropathy and nerve protein kinase C in rats Mizukami H, Ogasawara S, Yamagishi S, Takahashi K, Yagihashi S. Methylcobalamin effects on diabetic neuropathy and nerve protein kinase C in rats. Eur J Clin Invest. 2011 Apr;41(4):442-50. doi: 10.1111/j.1365-2362.2010.02430.x. Epub 2010 Dec 3. PubMed PMID: 21128935. BACKGROUND: Methyl-base-attached cobalamin (Methycobalamin) (MC) has a special affinity for nerve tissues to promote myelination and transport of axonal cytoskeleton. It is not known, however, how MC influences on peripheral nerve in experimental diabetic neuropathy. MATERIALS AND METHODS: We studied the effects of MC on expressions and activities of protein kinase C (PKC) in peripheral nerve of streptozotocin-induced diabetic rats. Wistar rats, 8 weeks of age, were rendered diabetic by streptozotocin (40 mg kg(-1), iv) and followed for 16 weeks. A half of diabetic animals were treated with MC (10 mg kg(-1) per every other day, im) after the induction of diabetes. Normal Wistar rats were served as control. RESULTS: At the end, untreated diabetic animals developed significant delay of nerve conduction velocity (NCV), and MC treatment normalized the NCV. Nerve PKC activity was significantly suppressed in untreated diabetic rats, while the activity was normalized in treated animals. While PKCα located in Schwann cells, PKCβΙα and βII distributed in axoplasm, vascular walls and macrophages. The decreased PKC activity in diabetic nerve was associated with reduced expression of membrane PKCα and increased membrane expression of PKCβII, and MC treatment corrected these changes. Diabetic nerve contained an increased number of macrophages and 8-hydroxydeoxyguanosine-positive cells in the endoneurium, the latter of which was significantly suppressed by MC treatment. Elevated nerve polyol levels in diabetic nerve were partially corrected by MC treatment. CONCLUSIONS: This study suggested that correction of impaired neural signalling of PKC and oxidative stress-induced damage may be a major attribute to the beneficial effects of MC on diabetic nerve."


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"Old or new medicine? Vitamin B12 and peripheral nerve neuropathy Tanaka H. [Old or new medicine? Vitamin B12 and peripheral nerve neuropathy]. Brain Nerve. 2013 Sep;65(9):1077-82. Review. Japanese. PubMed PMID: 24018744. Methylcobalamin is a vitamin B12 analog that is necessary for nervous system maintenance. Although methylcobalamin has some positive effects on peripheral nervous system disorders, the mechanism through which it affects neurons are not entirely known. Recent studies have revealed its intracellular signaling pathway and some of its molecular actions on neurons. In this article, I review interactions between methylcobalamin and neurons that have been revealed through in vitro studies, in vivo studies, and clinical use. Methylcobalamin participates in nervous system maintenance through several mechanisms. Methylcobalamin is an active form of vitamin B12, and a coenzyme of methionine synthase, which is required for DNA and protein methylation. In addition, methylcobalamin facilitates neurite outgrowth and inhibits neural apoptosis through the Erk1/2 and Akt signaling pathways. Treatment with high doses of methylcobalamin ameliorates symptoms and negative electrophysiological findings in animal models of peripheral nerve neuropathy and in patients with carpal tunnel syndrome and amyotrophic lateral sclerosis. Thus, high-dose methylcobalamin has great potential for treating nervous system disorders. Further investigations with methylcobalamin may help elucidate its mechanisms of action, which may further enable us to treat many nervous system disorders."


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"Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy Watanabe T, Kaji R, Oka N, Bara W, Kimura J. Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy. J Neurol Sci. 1994 Apr;122(2):140-3. PubMed PMID: 8021696. Despite intensive searches for therapeutic agents, few substances have been convincingly shown to enhance nerve regeneration in patients with peripheral neuropathies. Recent biochemical evidence suggests that an ultra-high dose of methylcobalamin (methyl-B12) may up-regulate gene transcription and thereby protein synthesis. We examined the effects of ultra-high dose of methyl-B12 on the rate of nerve regeneration in rats with acrylamide neuropathy, using the amplitudes of compound muscle action potentials (CMAPs) after tibial nerve stimulation as an index of the number of regenerating motor fibers. After intoxication with acrylamide, all the rats showed equally decreased CMAP amplitudes. The animals were then divided into 3 groups; rats treated with ultra-high (500 micrograms/kg body weight, intraperitoneally) and low (50 micrograms/kg) doses of methyl-B12, and saline-treated control rats. Those treated with ultra-high dose showed significantly faster CMAP recovery than saline-treated control rats, whereas the low-dose group showed no difference from the control. Morphometric analysis revealed a similar difference in fiber density between these groups. Ultra-high doses of methyl-B12 may be of clinical use for patients with peripheral neuropathies."


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"Neuroenhancement with Vitamin B12—Underestimated Neurological Significance Gröber U, Kisters K, Schmidt J. Neuroenhancement with Vitamin B12—Underestimated Neurological Significance. Nutrients. 2013;5(12):5031-5045. doi:10.3390/nu5125031. Vitamin B12 is a cofactor of methionine synthase in the synthesis of methionine, the precursor of the universal methyl donor S-Adenosylmethionine (SAMe), which is involved in different epigenomic regulatory mechanisms and especially in brain development. A Vitamin B12 deficiency expresses itself by a wide variety of neurological manifestations such as paraesthesias, skin numbness, coordination disorders and reduced nerve conduction velocity. In elderly people, a latent Vitamin B12 deficiency can be associated with a progressive brain atrophy. Moderately elevated concentrations of homocysteine (>10 µmol/L) have been associated with an increased risk of dementia, notably Alzheimer’s disease, in many cross-sectional and prospective studies. Raised plasma concentrations of homocysteine is also associated with both regional and whole brain atrophy, not only in Alzheimer’s disease but also in healthy elderly people. Clinician awareness should be raised to accurately diagnose and treat early Vitamin B12 deficiency to prevent irreversible structural brain damage."


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"Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse Yamazaki K, Oda K, Endo C, Kikuchi T, Wakabayashi T. Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse. Neurosci Lett. 1994 Mar 28;170(1):195-7. PubMed PMID: 8041506. We examined the effects of methylcobalamin (methyl-B12, mecobalamin) on degeneration of motor nerve terminals in the anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mice. GAD mice received orally methyl-B12 (1 mg/kg body wt/day) from the 40th day after birth for 25 days. In the distal endplate zone of the muscle, although most terminals were degenerated in both the untreated and methyl-B12-treated GAD mice, sprouts were more frequently observed in the latter. In the proximal endplate zone, where few degenerated terminals were seen in both groups of the mice, the perimeter of the terminals was increased and the area of the terminals was decreased significantly in the methyl-B12-treated GAD mice. These findings indicate that methyl-B12 promotes regeneration of degenerating nerve terminals in GAD mice."


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"Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy Ide H, et al. Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy. Clin Ther. 1987;9(2):183-92. PubMed PMID: 3568063. Seven men and four women with symptomatic diabetic neuropathy were treated with methylcobalamin (2,500 micrograms in 10 ml of saline) injected intrathecally. Treatment was begun when patients had good metabolic control, as determined by measurements of plasma glucose and hemoglobin, and was repeated several times with a one-month interval between injections. Three patients were re-treated one year after the last intrathecal injection. Symptoms in the legs, such as paresthesia, burning pains, and heaviness, dramatically improved. The effect appeared within a few hours to one week and lasted from several months to four years. The mean peroneal motor-nerve conduction velocity did not change significantly. The mean (+/- SD) concentration of methylcobalamin in spinal fluid was 114 +/- 32 pg/ml before intrathecal injection (n = 5) and 4,752 +/- 2,504 pg/ml one month after intrathecal methylcobalamin treatment (n = 11). Methylcobalamin caused no side effects with respect to subjective symptoms or characteristics of spinal fluid. These findings suggest that a high concentration of methylcobalamin in spinal fluid is highly effective and safe for treating the symptoms of diabetic neuropathy."


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"Effects of methylcobalamin on diabetic neuropathy Yaqub BA, Siddique A, Sulimani R. Effects of methylcobalamin on diabetic neuropathy. Clin Neurol Neurosurg. 1992;94(2):105-11. PubMed PMID: 1324807. We studied the clinical and neurophysiological effects of methylcobalamin on patients with diabetic neuropathy. In a double-blind study, the active group showed statistical improvement in the somatic and autonomic symptoms with regression of signs of diabetic neuropathy. Motor and sensory nerve conduction studies showed no statistical improvement after 4 months. The drug was easily tolerated by the patients and no side effects were encountered."


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"Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy Watanabe T, Kaji R, Oka N, Bara W, Kimura J. Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy. J Neurol Sci. 1994 Apr;122(2):140-3. PubMed PMID: 8021696. Despite intensive searches for therapeutic agents, few substances have been convincingly shown to enhance nerve regeneration in patients with peripheral neuropathies. Recent biochemical evidence suggests that an ultra-high dose of methylcobalamin (methyl-B12) may up-regulate gene transcription and thereby protein synthesis. We examined the effects of ultra-high dose of methyl-B12 on the rate of nerve regeneration in rats with acrylamide neuropathy, using the amplitudes of compound muscle action potentials (CMAPs) after tibial nerve stimulation as an index of the number of regenerating motor fibers. After intoxication with acrylamide, all the rats showed equally decreased CMAP amplitudes. The animals were then divided into 3 groups; rats treated with ultra-high (500 micrograms/kg body weight, intraperitoneally) and low (50 micrograms/kg) doses of methyl-B12, and saline-treated control rats. Those treated with ultra-high dose showed significantly faster CMAP recovery than saline-treated control rats, whereas the low-dose group showed no difference from the control. Morphometric analysis revealed a similar difference in fiber density between these groups. Ultra-high doses of methyl-B12 may be of clinical use for patients with peripheral neuropathies."


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"Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture Kikuchi M, et al. Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture. Invest Ophthalmol Vis Sci. 1997 Apr;38(5):848-54. PubMed PMID: 9112980. PURPOSE: To examine the effects of methylcobalamin on glutamate-induced neurotoxicity in the cultured retinal neurons. METHODS: Primary cultures obtained from the fetal rat retina (gestation days 16 to 19) were used for the experiment. The neurotoxicity was assessed quantitatively using the trypan blue exclusion method. RESULTS: Glutamate neurotoxicity was prevented by chronic exposure to methylcobalamin and S-adenosylmethionine (SAM), which is formed in the metabolic pathway of methylcobalamin. Chronic exposure to methylcobalamin and SAM also inhibited the neurotoxicity induced by sodium nitroprusside that release nitric oxide. By contrast, acute exposure to methylcobalamin did not protect retinal neurons against glutamate neurotoxicity. CONCLUSIONS: Chronic administration of methylcobalamin protects cultured retinal neurons against N-methyl-D-aspartate-receptor-mediated glutamate neurotoxicity, probably by altering the membrane properties through SAM-mediated methylation."


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"A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6. PubMed PMID: 8886748. In a double-blind, randomized, controlled study, the effectiveness of treatment with a combination of Benfotiamine (an Allithiamine, a lipid-soluble derivative of vitamin B1 with high bioavailability) plus vitamin B6/B12 on objective parameters of neuropathy was studied over a period of 12 weeks on 24 diabetic patients with diabetic polyneuropathy. The results showed a significant improvement (p = 0.006) of nerve conduction velocity in the peroneal nerve and a statistical trend toward improvement of the vibration perception threshold. Long-term observation of 9 patients with verum over a period of 9 months support the results. Therapy-specific adverse effects were not seen. The results of this double-blind investigation, of the long-term observation and of the reports in the literature support the contention that the neurotropic benfotiamine-vitamin B combination represents a starting point in the treatment of diabetic polyneuropathy."


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Vitamin E

"Treatment of diabetes mellitus-associated neuropathy with vitamin E and Eve primrose Ogbera AO, Ezeobi E, Unachukwu C, Oshinaike O. Treatment of diabetes mellitus-associated neuropathy with vitamin E and Eve primrose. Indian Journal of Endocrinology and Metabolism. 2014;18(6):846-849. doi:10.4103/2230-8210.140270. Background: The aim of this report was to assess the efficacy and safety of a combination of vitamin E, an antioxidant, and Eve Primrose in the management of painful diabetes mellitus (DM) neuropathy. Materials and Methods: This was an interventional study that evaluated the efficacy and safety of a combination of vitamin E and Eve Primrose in the management of DM neuropathy. The study was conducted at the Diabetic Centre of the Lagos State University Teaching Hospital, Ikeja. Eighty individuals with type 2 DM who had painful neuropathy were recruited for this study, which took place for a duration of 1 year. The study subjects underwent clinical and biochemical assessment at baseline and were given vitamin E in a dose of 400 mg in combination with Eve Primrose in doses ranging 500-1000 mg/day. They were afterward assessed for relief of symptoms and possible untoward effects after 2 weeks and, thereafter, monthly for 3 months. The main outcome measure was amelioration of symptoms of neuropathy. Results: The mean age and age range of the study subjects were 58.2 years and 37-70 years, respectively. A total of 70 patients (88%) of the study population reported relief from neuropathic pains. Clinical parameters were comparable between the responders and non-responders. One characteristic feature of the non-responders was that they all had vibration perception threshold of ≥25 mV, which was indicative of severe neuropathy. Conclusion: The combination of vitamin E and Eve Primrose is beneficial in the management of mild to moderate diabetic neuropathy."


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"Supplemental therapy in isolated vitamin E deficiency improves the peripheral neuropathy and prevents the progression of ataxia Martinello F, et al. Supplemental therapy in isolated vitamin E deficiency improves the peripheral neuropathy and prevents the progression of ataxia. J Neurol Sci. 1998 Apr 1;156(2):177-9. PubMed PMID: 9588854. A 24-year-old male, who suffered since childhood from a progressive form of ataxia associated with peripheral neuropathy, was found severely deficient in serum vitamin E. He walked with bilateral aid and presented severe dysmetria of the limbs and dysarthric speech; muscular strength and trophism were slightly diminished in the distal muscles of four limbs and there was hypotonia of the arms; he presented absent deep tendon reflexes, bilateral Babinski's sign, reduced proprioception at four limbs, pes cavus and fasciculations of the tongue. Intestinal fat malabsorption and other gastrointestinal or haematological conditions associated with deficiency of this vitamin were ruled out. In this patient, after 2 years of a daily supplement of high doses of vitamin E, a further progression of the disease was not observed and, moreover, the neurophysiological characteristics of his neuropathy appeared clearly improved. A longitudinal evaluation of serum vitamin E levels showed values in the normal range after 13 months of therapy. The patient had molecular genetic analysis of chromosome 8 and was found homozygous for the unusual mutation 513insTT in the alpha-tocopherol transfer protein gene."


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"Analgesic effect of vitamin E is mediated by reducing central sensitization in neuropathic pain Kim HK, et al. Analgesic effect of vitamin E is mediated by reducing central sensitization in neuropathic pain. Pain. 2006 May;122(1-2):53-62. Epub 2006 Mar 9. PubMed PMID: 16524661. Recent studies suggest that reactive oxygen species (ROS) are critically involved in neuropathic pain. Although vitamin E is a well-known antioxidant, its efficacy on chronic pain is not known. This study investigated the efficacy and mechanisms of vitamin E analgesia in a rat model of neuropathic pain produced by spinal nerve ligation. The effects of vitamin E were investigated using behavioral testing, electrophysiological recording of dorsal horn neurons, and determinations of phosphorylated NMDA receptor subunit 1 (pNR1) levels in the spinal dorsal horn. Results showed that a systemic single injection of a high dose or repetitive daily injections of low doses of vitamin E significantly reduced neuropathic pain behaviors. Vitamin E was also effective in producing analgesia by intrathecal injection, suggesting the importance of spinal mechanisms. In spinal dorsal horn neurons, vitamin E reduced evoked responses to mechanical stimuli as well as the sizes of their receptive fields. In addition, levels of pNR1 in neuropathic rats were also reduced by vitamin E injection. These data suggest that vitamin E produces analgesia in neuropathic rats that is, at least in part, mediated by reducing central sensitization which, in turn, is induced by peripheral nerve injury."


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"Peripheral Neuropathy Due to Vitamin Deficiency, Toxins, and Medications. Continuum : Lifelong Learning in Neurology Staff NP, Windebank AJ. Peripheral Neuropathy Due to Vitamin Deficiency, Toxins, and Medications. Continuum : Lifelong Learning in Neurology. 2014;20(5 Peripheral Nervous System Disorders):1293-1306. doi:10.1212/01.CON.0000455880.06675.5a. While the primary neurologic deficit in vitamin E deficiency is a spinocerebellar syndrome, there is often a concomitant large fiber sensory-predominant axonal peripheral neuropathy. Vitamin E deficiency occurs in the setting of severe fat malabsorption (eg, biliary dysfunction, cystic fibrosis) or genetic disorders (eg, ataxia with vitamin E deficiency or abetalipoproteinemia). Strategies to treat vitamin E deficiency include improving fat absorption and oral vitamin E supplementation."


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"Reversal of defective nerve conduction with vitamin E supplementation in type 2 diabetes: a preliminary study Tütüncü NB, Bayraktar M, Varli K. Reversal of defective nerve conduction with vitamin E supplementation in type 2 diabetes: a preliminary study. Diabetes Care. 1998 Nov;21(11):1915-8. PubMed PMID: 9802743. OBJECTIVE: The present study has examined the effect of vitamin E, the principal modulator of free radical activity, on electrophysiological parameters in patients with diabetic peripheral sensorimotor polyneuropathy, matched for duration of disease and metabolic control. RESEARCH DESIGN AND METHODS: A total of 21 subjects with type 2 diabetes were enrolled in this double-blind randomized placebo-controlled study (vitamin E, 11 patients; placebo, 10 patients). Patients were randomly assigned to receive either 900 mg vitamin E or placebo for 6 months. The average dietary vitamin E consumption of the subjects was similar during the study. The main outcome measure was the electrophysiological tests assessing nerve conduction. Fasting plasma glucose, HbA1, postprandial plasma glucose, and electrophysiological parameters in the basal state and after 6 months of treatment were studied. RESULTS: Glycemic indexes did not show any significant changes during the study, whereas nerve conduction improved significantly in 2 of the 12 studied electrophysiological parameters after 6 months in patients on vitamin E supplementation. The changes in the electrophysiological parameters were obvious in the median motor nerve fibers and tibial motor nerve fibers. Nerve conduction velocity in the median motor nerve fibers (P = 0.0019) and tibial motor nerve distal latency (P = 0.0284) improved significantly after 6 months of vitamin E supplementation. CONCLUSIONS: This study shows that defective nerve conduction in diabetic subjects with mild-to-moderate peripheral neuropathy may be improved by pharmacological doses of vitamin E supplementation. Further studies with a larger number of patients for longer periods of time are needed."


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"A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against cisplatin-induced peripheral neuropathy: final results Argyriou AA, et al. A randomized controlled trial evaluating the efficacy and safety of vitamin E supplementation for protection against cisplatin-induced peripheral neuropathy: final results. Support Care Cancer. 2006 Nov;14(11):1134-40. Epub 2006 Apr 19. PubMed PMID: 16622646. AIM: A randomized, open label with blind assessment, controlled trial was performed to assess efficacy and adverse-event profile of vitamin E, given as supplementation for prophylaxis against cisplatin-induced peripheral neuropathy (CIPN). PATIENTS AND METHODS: A total of 30 patients scheduled to receive six courses of cumulative cisplatin-based regimens were randomly allocated to treatment and control groups and were then studied by means of neurological examination and electrophysiological study. Patients assigned to group I (n=14) orally received vitamin E at a daily dose of 600 mg/day during chemotherapy and 3 months after its cessation were compared to patients of group II (n=16), who received no vitamin E supplementation and served as controls. The severity of neurotoxicity was summarized by means of a modified Peripheral Neuropathy (PNP) score. RESULTS: The incidence of neurotoxicity differed significantly between groups, occurring in 3/14 (21.4%) of patients assigned to the vitamin E supplementation group and in 11/16 (68.5%) of controls (p=0.026). The relative risk (RR) of developing neurotoxicity was significantly higher in case of controls, RR=2.51, 95% C.I.=1.16-5.47. Mean PNP scores were 4.99+/-1.33 for patients of group I and 10.47+/-10.62 for controls, (p=0.023). None of the adverse events or deaths occurred, were judged as likely to be related to the vitamin E supplementation. CONCLUSION: Vitamin E effectively and safely protects patients with cancer from occurrence of cisplatin neurotoxicity."


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Vitamin D

"Reversal of the Symptoms of Diabetic Neuropathy through Correction of Vitamin D Deficiency in a Type 1 Diabetic Patient Bell DSH. Reversal of the Symptoms of Diabetic Neuropathy through Correction of Vitamin D Deficiency in a Type 1 Diabetic Patient. Case Reports in Endocrinology. 2012;2012:165056. doi:10.1155/2012/165056. Vitamin D deficiency has been associated with both type 1 and type 2 diabetes as well as both the microvascular and macrovascular complications of diabetes. Vitamin D deficiency has been shown to be more common in diabetic patients who have symptoms of distal symmetrical polyneuropathy. In addition, vitamin D deficiency has been associated with a lower pain threshold which increases when vitamin D deficiency is corrected. Herein, I describe a type 1 diabetic patient with neuropathic symptoms so severe that he could not work and for which he needed narcotics for pain management and whose symptoms improved dramatically with correction of the vitamin D deficiency. To my knowledge, this is the first report of an improvement in severe symptoms of diabetic neuropathy with correction of vitamin D deficiency in a single patient."


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"Does Vitamin D deficiency play a role in peripheral neuropathy in Type 2 diabetes? Shehab D, Al-Jarallah K, Mojiminiyi OA, Al Mohamedy H, Abdella NA. Does Vitamin D deficiency play a role in peripheral neuropathy in Type 2 diabetes? Diabet Med. 2012 Jan;29(1):43-9. doi: 10.1111/j.1464-5491.2011.03510.x. PubMed PMID: 22050401. AIM: Despite recent reports linking vitamin D deficiency with increased risk of diabetes mellitus and complications, there is limited data on patients with diabetic peripheral neuropathy. We aimed to evaluate the incidence and associations of vitamin D deficiency in 210 patients with Type 2 diabetes with and without diabetic peripheral neuropathy. METHODS: Renal, liver, lipid profile and HbA(1c) were measured. Vitamin D status was determined by measuring 25-dihydroxyvitamin D. Presence or absence of coronary heart disease was determined and early-morning urine microalbumin:creatinine ratio was measured. All patients were assessed clinically using neuropathy symptom score, neuropathy disability score and nerve conduction study. RESULTS: Eighty-seven patients had diabetic peripheral neuropathy and these patients had significantly longer duration of diabetes and higher HbA(1c). Age, gender, incidence of retinopathy and coronary heart disease were not significantly different from those without neuropathy. Mean (SD) vitamin D was significantly lower in those with neuropathy [36.9 (39.9) nmol/l] compared with those without [58.32 (58.9) nmol/l] and 81.5% of patients with neuropathy had vitamin D deficiency compared with 60.4% of those without. Vitamin D showed significant (P < 0.05) correlations with total cholesterol, LDL-cholesterol and urine microalbumin:creatinine ratio. Binary logistic regression analysis showed that diabetic peripheral neuropathy was significantly associated with vitamin D deficiency (odds ratio = 3.47; 95% CI = 1.04-11.56, P = 0.043) after inclusion of potential confounders such as duration of diabetes, HbA(1c) and LDL-cholesterol. CONCLUSION: Vitamin D deficiency is an independent risk factor for diabetic peripheral neuropathy, and further studies are required to confirm if Vitamin D supplementation could prevent or delay the onset."


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"Vitamin D for the treatment of painful diabetic neuropathy Basit A, et al. Vitamin D for the treatment of painful diabetic neuropathy. BMJ Open Diabetes Research & Care. 2016;4(1):e000148. doi:10.1136/bmjdrc-2015-000148. Treatment with a single intramuscular dose of 600 000 IU of vitamin D in patients with painful diabetic neuropathy is associated with a significant decrease in the symptoms of painful diabetic neuropathy."


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"Association between vitamin D and diabetic neuropathy in a nationally representative sample: results from 2001–2004 NHANES Soderstrom LH, Johnson SP, Diaz VA, Mainous AG. Association between vitamin D and diabetic neuropathy in a nationally representative sample: results from 2001–2004 NHANES. Diabetic medicine : a journal of the British Diabetic Association. 2012;29(1):50-55. doi:10.1111/j.1464-5491.2011.03379.x. Aims To evaluate the association between vitamin D insufficiency and peripheral neuropathy in a nationally representative sample of adults with diagnosed diabetes. Methods Vitamin D concentrations, medical examination variables and questionnaire results from the 2001–2004 National Health and Nutrition Examination Survey were analysed for adults ≥ 40 years old with diagnosed diabetes (unweighted n = 591, weighted n = 8.82 million). Neuropathy was defined as self report of peripheral neuropathy symptoms of painful sensation, tingling, numbness or loss of feeling in hands or feet. Additionally, Semmes–Weinstein monofilament test results were used as an indicator of neuropathy. Insufficient vitamin D was characterized as < 30 ng/ml. Results In the weighted population, 81% of adults with diabetes had vitamin D insufficiency. Vitamin D insufficiency was more common among Hispanics (92%) and non-Hispanic black people (98%) than among non-Hispanic white people (76%). Within the 3 months preceding the questionnaire, 50% reported experiencing pain or numbness (paresthesia) in their hands or feet; 37% reported pain or tingling in hands or feet; and 38% reported numbness or loss of feeling in hands or feet. Eight per cent had 4–6 insensate areas on their feet as determined by the Semmes– Weinstein monofilament test. Logistic regressions demonstrate vitamin D insufficiency is associated with the adjusted composite paresthesia measure (odds ratio 2.12; 95% CI 1.17–3.85) and the adjusted numbness measure (odds ratio 2.04; 95% CI 1.18–3.52). Conclusions Vitamin D insufficiency is associated with self-reported peripheral neuropathy symptoms even after adjusting for demographic factors, obesity, co-morbidities, use of medications for neuropathy and diabetes duration and control."


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"Vitamin D and Diabetic Complications: True or False Prophet? Alam U, Arul-Devah V, Javed S, Malik RA. Vitamin D and Diabetic Complications: True or False Prophet? Diabetes Therapy. 2016;7(1):11-26. doi:10.1007/s13300-016-0159-x. Vitamin D deficiency is now recognized as a condition of increasing prevalence worldwide. Vitamin D has an established role in calcium and bone metabolism; however, more recently associations with vitamin D deficiency and risk of developing diabetes, diabetes complications, and cardiovascular disease have all been acknowledged. The vitamin D receptor is ubiquitously expressed, and experimental, in vitro, and in vivo studies strongly suggest a role in regulating the transcription of multiple genes beyond calcium homeostasis. These include antiproliferative, immunomodulatory, angiogenic, inhibition of the renin–angiotensin–aldosterone system, and neurotrophic factor expression. Observational studies report a strong association between vitamin D deficiency and cardiovascular and metabolic disorders; however, there remains a paucity of large long-term randomized clinical trials showing a benefit with treatment. An increasing body of literature suggests a possible pathogenetic role of vitamin D in the long-term complications of diabetes and vitamin D deficiency may also exacerbate symptoms of painful diabetic peripheral neuropathy. It remains unknown if supplementation of vitamin D to normal or non-deficient levels alters pathogenetic processes related to diabetic microvascular complications. With the high prevalence of vitamin D deficiency in patients with diabetes and putative mechanisms linking vitamin D deficiency to diabetic complications, there is a compelling argument for undertaking large well-designed randomized controlled trials of vitamin D supplementation."


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"Low serum vitamin D occurs commonly among multiple myeloma patients treated with bortezomib and/or thalidomide and is associated with severe neuropathy Wang J, et al. Low serum vitamin D occurs commonly among multiple myeloma patients treated with bortezomib and/or thalidomide and is associated with severe neuropathy. Support Care Cancer. 2016 Jul;24(7):3105-10. doi: 10.1007/s00520-016-3126-1. Epub 2016 Feb 23. PubMed PMID: 26902977. PURPOSE: Previous studies have shown that low serum vitamin D levels have been associated with many skeletal and non-skeletal disorders. We studied the relationship between 25-hydroxyvitamin D (25D) levels and motor and sensory peripheral neuropathy (PN) among multiple myeloma (MM) patients who have been treated with bortezomib and/or thalidomide. METHODS: We performed a study of 111 MM patients who had received at least one of these two agents for at least 12 weeks by correlating physical exam/neurologic assessment findings with patient self-assessment responses. RESULTS: The median age of study patients was 66 years (range 42-89 years) and 54 % were males. 25D levels were determined, and complete history and physical and neurologic examinations were performed at the same study visit. In addition, study subjects completed questionnaires regarding symptoms related to motor and sensory PN. Overall, patients had a median serum 25D level of only 32 ng/ml; 42 % of patients were considered either 25D-deficient (< 20.0 ng/mL; 16 % of patients) or 25D-insufficient (20.0-29.9 ng/mL; 26 %). Notably, we found that 25D-deficient MM patients were more likely to have severe PN (>grade 2) of both motor (p = 0.0415) and sensory (p = 0.0086) types although the overall incidence of PN was not higher in this patient population. CONCLUSION: These results show that the severity of peripheral neuropathy is associated with lower vitamin D levels and provides the rationale for monitoring vitamin D for myeloma patients especially those receiving drugs associated with the development of peripheral neuropathy."


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"The association of vitamin D with inflammatory cytokines in diabetic peripheral neuropathy Bilir B, et al. The association of vitamin D with inflammatory cytokines in diabetic peripheral neuropathy. Journal of Physical Therapy Science. 2016;28(7):2159-2163. doi:10.1589/jpts.28.2159. [Purpose] The effects of vitamin D on the circulating levels of IL-17 and IL-13 were investigated in patients with diabetic peripheral neuropathy, patients with diabetes mellitus type 2 without neuropathy, and healthy controls. [Subjects and Methods] A single-blind controlled clinical study was performed, including70 type 2 diabetic patients with or without diabetic peripheral neuropathy and 33 healthy volunteer controls. The 25(OH)D levels were evaluated using ultra-performance liquid chromatography, and IL-17 and IL-13 levels were assessed using enzyme-linked immunosorbent assays. [Results] The 25(OH) vitamin D concentration was lower in diabetic peripheral neuropathy patients than in diabetes mellitus patients without neuropathy and healthy controls. Similarly, 25(OH)D levels were lower in diabetes mellitus patients than healthy controls. IL-17 and IL-13 levels were higher in diabetes mellitus patients than in controls. Additionally, IL-13 levels were higher in diabetic peripheral neuropathy patients than in diabetes mellitus patients without neuropathy. These differences were statistically significant. There was a significant positive correlation between 25(OH)D and IL-13,and a negative correlation between 25(OH)D andIL-17 in the diabetic and diabetic neuropathy groups. [Conclusion] Vitamin D is a potential modifiable risk factor for diabetic peripheral neuropathy and may regulate inflammatory mediators, e.g., IL-17 and IL-13."


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"The association between vitamin D level and diabetic peripheral neuropathy in patients with type 2 diabetes mellitus: An update systematic review and meta-analysis Guang-Bo Qu, Ling-Ling Wang, Xue Tang, Wei Wu, Ye-Huan Sun. The association between vitamin D level and diabetic peripheral neuropathy in patients with type 2 diabetes mellitus: An update systematic review and meta-analysis. Journal of Clinical & Translational Endocrinology, Volume 9, 2017, Pages 25-31, ISSN 2214-6237. Aim Recently, increasing studies have been carried out to explore the association between vitamin D level and the development of diabetic peripheral neuropathy (DPN) in patients with diabetes mellitus (DM). However, because of the shortcoming in study design and sample size, there is still no clear conclusion. We performed this meta-analysis to examine the exact impact of vitamin D deficiency on DPN in type 2 diabetic patients. Methods Various databases were searched to identify the potential articles which explored the association between vitamin D level and diabetic peripheral neuropathy in type 2 diabetes. We pooled OR to assess the correlation between vitamin D deficiency and DPN using the random-effects model. The standardized mean difference (SMD) with 95% CI of vitamin D was also calculated to evaluate the vitamin D level between DPN and non DPN in T2DM. Results There was obvious heterogeneity in those included ten studies (I2 = 94.1%, Cochran Q test P < 0.001) using mean and standard deviation (SD) of vitamin D level. In Caucasian, vitamin D level was significantly lower in DPN patients compared with diabetic patients without DPN (SMD = −0.56, I2 = 16.9%). In Asian, the pooled OR value of vitamin D deficiency was 1.22 (95%CI: 1.17–1.27). Sensitivity analysis showed one study had great influence on this meta-analysis and it still existed after excluded that one. There was no evidence of public bias in meta analysis as showed in Begg test and Egger test. Conclusion This meta-analysis indicates that vitamin D deficiency is associated with the generation and development of DPN in Caucasian with T2DM, and in Asian, diabetic patients with vitamin D deficiency are 1.22 times to suffer from DPN compared with normal vitamin D level. Vitamin D supplementation is urgently needed to prevent the development of DPN in T2DM."


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Magnesium Bisglycinate Chelate TRAACS

"Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg-depleted type 1 diabetic patients (T1dm) De Leeuw I, Engelen W, De Block C, Van Gaal L. Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg-depleted type 1 diabetic patients (T1dm). Magnes Res. 2004 Jun;17(2):109-14. PubMed PMID: 15319143. Chronic Mg depletion in T1dm has been linked to polyneuropathy (PNP). Short term Mg supplementation has suggested a decrease in pathological EMG signs typical for PNP. The aim of this study is to determine if long term supplementation under stable metabolic control can normalize the Mg status and influence the natural evolution of PNP. 110 T1dm (60 M,50 W) with chronic Mg depletion (erythrocyte Mg < 2.3 mMol/l) were randomised to receive 300 mg Mg++ daily or no supplement for a period of 5 years. Follow-up was organized by the same diabetologist: HbA1c, renal function and Mg status every 3 months, electromyography (EMG) and clinical neurological control with staging every year. Drop-out was decided for recurrent DKA, diseases or drugs interfering with Mg status or side-effects of Mg treatment. 97 patients (53 M,44 W) finished the study: 49 (27 M,22W) were supplemented (group A) and 48 (26 M,22 W) served as controls (group B). At the start there were no significant differences between both groups. HbA1c after 5 years (A:7.80% sd 0.80, B:7.75% sd 0.75) was not significantly different from the start. Erythrocyte Mg (Mg rbc) rose significantly (p < 0.0001) in group A to normal levels but remained low in group B. Staging of PNP after 5 years shows a decrease in 39%, statu quo in 49% and a worsening in 12% in group A and 8,31 and 61% respectively in group B (Fisher Exact test: p < 0.0001). Normalization of EMG signs was only seen in incipient PNP. Logistic regression analysis shows that longer duration of diabetes (p < 0.006) and low Mgrbc (p < 0.05) are the major determinants of PNP evolution. Under stable metabolic control long term Mg supplementation is able to restore a normal Mg status and influence favourably the natural evolution of PNP as compared to non supplemented T1dm controls."


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"MAGnesium-oral supplementation to reduce PAin in patients with severe PERipheral arterial occlusive disease: the MAG-PAPER randomised clinical trial protocol Venturini MA, et al. MAGnesium-oral supplementation to reduce PAin in patients with severe PERipheral arterial occlusive disease: the MAG-PAPER randomised clinical trial protocol. BMJ Open. 2015;5(12):e009137. doi:10.1136/bmjopen-2015-009137. Magnesium exerts analgaesic effects in several animal pain models, as well as in patients affected by acute postoperative pain and neuropathic chronic pain. There is no evidence that magnesium can modulate pain in patients with peripheral arterial occlusive disease (PAOD). We describe the protocol of a single-centre randomised double-blind clinical trial aimed at assessing the efficacy of oral magnesium supplementation in controlling severe pain in patients with advanced PAOD."


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"Relief of neuropathic pain with intravenous magnesium Tanaka M, et al. [Relief of neuropathic pain with intravenous magnesium]. Masui. 1998 Sep;47(9):1109-13. Japanese. PubMed PMID: 9785788. We investigated the effect of intravenous magnesium, a N-methyl-D-asparate (NMDA) receptor antagonist, in 8 patients suffering from neuropathic pain (post herpetic neuralgia or causalgia etc.). After the nerve block, magnesium sulphate (0.5 mol.l-1) 5 ml was administered intravenously by bolus infusion taking 5 min, followed by continuous infusion of the same dose for one hour. All patients were treated with this therapy once a week. In 4 patients, VAS score decreased 3 points or more when this therapy had been administered 3 to 11 times. In 2 patients, VAS score did not change, and the analgesic effect of magnesium was not certain in other 2 patients. Some patients felt heat sensation immediately after the bolus infusion of Mg, and had a good sleep after this therapy. However, there were not any severe side effects and significant change in HR or BP. We conclude that this therapy with magnesium once a week is safe and effective for relieving neuropathic pain."


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"Magnesium in Prevention and Therapy Gröber U, Schmidt J, Kisters K. Magnesium in Prevention and Therapy. Nutrients. 2015;7(9):8199-8226. doi:10.3390/nu7095388. Magnesium is the fourth most abundant mineral in the body. It has been recognized as a cofactor for more than 300 enzymatic reactions, where it is crucial for adenosine triphosphate (ATP) metabolism. Magnesium is required for DNA and RNA synthesis, reproduction, and protein synthesis. Moreover, magnesium is essential for the regulation of muscular contraction, blood pressure, insulin metabolism, cardiac excitability, vasomotor tone, nerve transmission and neuromuscular conduction. Imbalances in magnesium status—primarily hypomagnesemia as it is seen more common than hypermagnesemia—might result in unwanted neuromuscular, cardiac or nervous disorders. Based on magnesium’s many functions within the human body, it plays an important role in prevention and treatment of many diseases. Low levels of magnesium have been associated with a number of chronic diseases, such as Alzheimer’s disease, insulin resistance and type-2 diabetes mellitus, hypertension, cardiovascular disease (e.g., stroke), migraine headaches, and attention deficit hyperactivity disorder (ADHD)."


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"The effect of magnesium supplementation in increasing doses on the control of type 2 diabetes de Lordes Lima M, et al. The effect of magnesium supplementation in increasing doses on the control of type 2 diabetes. Diabetes Care. 1998 May;21(5):682-6. PubMed PMID: 9589224. OBJECTIVE: Hypomagnesemia occurs in 25-38% of patients with type 2 diabetes. Several studies have suggested an association between magnesium (Mg) depletion and insulin resistance and/or reduction of insulin secretion in these cases. Our purpose was to evaluate if Mg supplementation (as magnesium oxide [MgO]) would improve metabolic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We studied 128 patients with type 2 diabetes (32 men, 96 women, aged 30-69 years), treated by diet or diet plus oral antidiabetic drugs, in the Bahia Federal University Hospital, Brazil. Patients at risk for hypomagnesemia or with reduced renal function were excluded. This study was a clinical randomized double-blind placebo-controlled trial. Patients received either placebo, 20.7 mmol MgO, or 41.4 mmol MgO daily (elementary Mg) for 30 days. Mg concentrations were measured in plasma, in mononuclear cells, and in 24-h urine samples. Fasting blood glucose, HbA1, and fructosamine were used as parameters of metabolic control. RESULTS: Of the patients, 47.7% had low plasma Mg, and 31.1% had low intramononuclear Mg levels. Intracellular Mg in patients with diabetes was significantly lower than in the normal population (62 blood donors; 1.4 +/- 0.6 vs. 1.7 +/- 0.6 micrograms/mg of total proteins). No correlation was found between plasma and intracellular Mg concentrations (r = -0.179; P = 0.15) or between Mg concentrations and glycemic control (r = -0.165; P = 0.12). Intracellular Mg levels were lower in patients with peripheral neuropathy than in those without (1.2 +/- 0.5 vs. 1.5 +/- 0.6 micrograms/mg). Similar findings were observed in patients with coronary disease (1.0 +/- 0.5 vs. 1.5 +/- 0.6 micrograms/mg). In the placebo and in the 20.7 mmol Mg groups, neither a change in plasma and intracellular levels nor an improvement in glycemic control were observed. Replacement with 41.4 mmol Mg tended to increase plasma, cellular, and urine Mg and caused a significant fall (4.1 +/- 0.8 to 3.8 +/- 0.7 mmol/l) in fructosamine (normal, 1.87-2.87 mmol/l). CONCLUSIONS: Mg depletion is common in poorly controlled patients with type 2 diabetes, especially in those with neuropathy or coronary disease. More prolonged use of Mg in doses that are higher than usual is needed to establish its routine or selective administration in patients with type 2 diabetes to improve control or prevent chronic complications."


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There are a vast number of clinical studies over the last few decades that have shown the effectiveness of the ingredients found in NeuraZenx. Our clinical research team has compiled several of these studies with the results so that you can find out for yourself that the ingredients in NeuraZenx can help easing nerve pain and discomfort and support nerve health*.