NERVE ReGEN Scientific Research

Vitamin D

Reversal of the Symptoms of Diabetic Neuropathy through Correction of Vitamin D Deficiency in a Type 1 Diabetic Patient *


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.

Source: David S.H. Bell. “Reversal of the Symptoms of Diabetic Neuropathy through Correction of Vitamin D Deficiency in a Type 1 Diabetic Patient” Case Report (2012).

Does vitamin D supplementations improve peripheral diabetic neuropathy? A before-after clinical trial *


Objective: Peripheral neuropathy is a common complication of diabetes mellitus. This study was set to assess the effect of vitamin D supplementation on peripheral neuropathy in patients with type 2 diabetes (T2DM).

Materials and methods: This study was a quasi-experimental trial in Yazd diabetic research center. Sixty T2DM subjects (30-65 years old) with painful diabetic neuropathy enrolled in this study from March 2017 till April 2018. Patients received weekly 50000 IU of vitamin D3 for 12 weeks orally. Evaluation of diabetic neuropathy was performed by using Michigan Neuropathy Screening Instrument (MNSI) before and after trial. Also fasting plasma glucose, HbA1c, calcium and vitamin D checked before and after the trial. SPSS version 20 software was used for statistical analysis. P ≤ 0.05 was considered to be statistically significant.

Results: Among 60 T2DM patients, 58 completed the study. Most of them (53.4%) were male. At the end of study, HbA1c, vitamin D, MNSI (both questionnaire and physical examination) improved that is statistically significant (p-value: <0.001).

Conclusion: Oral supplementation of vitamin D 3 (50,000 IU) once weekly for 12 weeks was associated with improvement in the serum level of vitamin D and significant decrease in the symptoms and sign of diabetic neuropathy. So serum vitamin D level should be checked in persons with diabetic neuropathy and low levels of it should be corrected in order to reducing neuropathy severity.

Source: Akram Ghadiri-Anari, Zohre Mozafari, Somaye Gholami, Seyed-Ali Khodaei, Marzieh Aboutorabi-Zarchi, Fariba Sepehri , Azade Nadjarzade, Masoud Rahmanian, and Nasim Namiranian. “Dose vitamin D supplementations improve peripheral diabetic neuropathy? A before-after clinical trial” Diabetes and Metabolic Syndrome (2019): 13(1):890-893.

The association between vitamin D level and diabetic peripheral neuropathy in patients with type 2 diabetes mellitus: An update systematic review and meta-analysis *

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.

Source: Guang-Bo Qu, Ling-Ling Wang, Xue Tang, Wei Wu, and 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 and Translational Endocrinology. (2017): 9: 25–31.

Riboflavin (Vitamin B2)

Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience *


Introduction: Riboflavin (vitamin B2) is absorbed in the small intestine by the human riboflavin transporters RFVT1 and RFVT3. A third riboflavin transporter (RFVT2) is expressed in the brain. In 2010 it was demonstrated that mutations in the riboflavin transporter genes SLC52A2 (coding for RFVT2) and SLC52A3 (coding for RFVT3) cause a neurodegenerative disorder formerly known as Brown-Vialetto-Van Laere (BVVL) syndrome, now renamed to riboflavin transporter deficiency. Five years after the diagnosis of the first patient we performed a review of the literature to study the presentation, treatment and outcome of patients with a molecularly confirmed diagnosis of a riboflavin transporter deficiency.

Method: A search was performed in Medline, Pubmed using the search terms ‘Brown-Vialetto-Van Laere syndrome’ and ‘riboflavin transporter’ and articles were screened for case reports of patients with a molecular diagnosis of a riboflavin transporter deficiency.

Results: Reports on a total of 70 patients with a molecular diagnosis of a RFVT2 or RTVT3 deficiency were retrieved. The riboflavin transporter deficiencies present with weakness, cranial nerve deficits including hearing loss, sensory symptoms including sensory ataxia, feeding difficulties and respiratory difficulties which are caused by a sensorimotor axonal neuropathy and cranial neuropathy. Biochemical abnormalities may be absent and the diagnosis can only be made or rejected by molecular analysis of all genes. Treatment with oral supplementation of riboflavin is lifesaving. Therefore, if a riboflavin transporter deficiency is suspected, treatment must be started immediately without first awaiting the results of molecular diagnostics.

Source: Bregje Jaeger and Annet M. Bosch. “Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience” Journal of Inherited Metabolic Disease (2016): 39: 559–564.

Riboflavin (vitamin B-2) and health *


Riboflavin is unique among the water-soluble vitamins in that milk and dairy products make the greatest contribution to its intake in Western diets. Meat and fish are also good sources of riboflavin, and certain fruit and vegetables, especially dark-green vegetables, contain reasonably high concentrations. Biochemical signs of depletion arise within only a few days of dietary deprivation. Poor riboflavin status in Western countries seems to be of most concern for the elderly and adolescents, despite the diversity of riboflavin-rich foods available. However, discrepancies between dietary intake data and biochemical data suggest either that requirements are higher than hitherto thought or that biochemical thresholds for deficiency are inappropriate. This article reviews current evidence that diets low in riboflavin present specific health risks. There is reasonably good evidence that poor riboflavin status interferes with iron handling and contributes to the etiology of anemia when iron intakes are low. Various mechanisms for this have been proposed, including effects on the gastrointestinal tract that might compromise the handling of other nutrients. Riboflavin deficiency has been implicated as a risk factor for cancer, although this has not been satisfactorily established in humans. Current interest is focused on the role that riboflavin plays in determining circulating concentrations of homocysteine, a risk factor for cardiovascular disease. Other mechanisms have been proposed for a protective role of riboflavin in ischemia reperfusion injury; this requires further study. Riboflavin deficiency may exert some of its effects by reducing the metabolism of other B vitamins, notably folate and vitamin B-6.

Source: Hillary J. Powers. “Riboflavin (vitamin B-2) and health” The American Journal of Clinical Nutrition (2003): Volume 77, Issue 6, Pages 1352–1360.

Clinical, pathological and functional characterization of riboflavin-responsive neuropathy *


Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column-medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.

Source: Andreea Manole, Zane Jaunmuktane, Iain Hargreaves, Marthe H. R. Ludtmann, Vincenzo Salpietro, Oscar D Bello, Simon Pope, Amelie Pandraud, Alejandro Horga, Renata S. Scalco, Abi Li, Balasubramaniem Ashokkumar, Charles M. Lourenço, Simon Heales, Rita Horvath, Patrick F. Chinnery, Camilo Toro, Andrew B. Singleton, Thomas S. Jacques, Andrey Y. Abramov, Francesco Muntoni, Michael G Hanna, Mary M Reilly, Tamas Revesz, Dimitri M Kullmann, James E. C. Jepson, Henry Houlden. Clinical, pathological and functional characterization of riboflavin-responsive neuropathy” Brain (2017): 140(11):2820-2837.

Vitamin B12 (methylcobalamin)

Vitamin B supplementation for diabetic peripheral neuropathy *


Vitamin B12 deficiency has been associated with significant neurological pathology, especially peripheral neuropathy. This review aims to examine the existing evidence on the effectiveness of vitamin B12 supplementation for the treatment of diabetic peripheral neuropathy. A search of PubMed and the Cochrane Central Register of Controlled Trials for all relevant randomised controlled trials was conducted in December 2014. Any type of therapy using vitamin B12 or its coenzyme forms was assessed for efficacy and safety in diabetics with peripheral neuropathy. Changes in vibration perception thresholds, neuropathic symptoms and nerve conduction velocities, as well as the adverse effects of vitamin B12 therapy, were assessed. Four studies comprising 363 patients met the inclusion criteria. This review found no evidence that the use of oral vitamin B12 supplements is associated with improvement in the clinical symptoms of diabetic neuropathy. Furthermore, the majority of studies reported no improvement in the electrophysiological markers of nerve conduction.

Source: Bhavani Jayabalan, MBBS, MMed and Lian Leng Low, MBBS, MMed. “Vitamin B supplementation for diabetic peripheral neuropathy” Singapore Medical Journal (2016): 57(2): 55–59.

Vitamin B12 enhances nerve repair and improves functional recovery after traumatic brain injury by inhibiting ER stress-induced neuron injury*

Traumatic brain injury (TBI) is one of the most common causes of neurological damage in young human populations. Vitamin B12 has been reported to promote axon growth of neuronal cells after peripheral nerve injury, which is currently used for the treatment of peripheral nerve damage in the clinical trial. Thus, we hypothesized that TBI can be attenuated by vitaminB12 treatment through its beneficial role on axon regeneration after nerve injury. To confirm it, the biological function of vitamin B12 was characterized using hematoxylin and eosin (H&E) staining, Luxol fast blue (LFB) staining, western blot analysis, and immunohistochemistry staining. The results showed that the neurological functional recovery was improved in the VitaminB12-treated group after TBI, which may be due to downregulation of the endoplasmic reticulum stress-related apoptosis signaling pathway. Moreover, the microtubule stabilization, remyelination and myelin reparation were rescued by vitamin B12, which was consistent with the treatment of 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum stress inhibitor. The study suggests that vitamin B12 may be useful as a novel neuroprotective drug for TBI.

Source: Fangfang Wu, Ke Xu, Lei Liu, Kairui Zhang, Leilei Xia, Man Zhang, Chenhuai Teng, Heyan Tong, Yifang He, Yujie Xue, Hongyu Zhang, Daqing Chen and Aiping Hu. “Vitamin B12 Enhances Nerve Repair and Improves Functional Recovery After Traumatic Brain Injury by Inhibiting ER Stress-Induced Neuron Injury” Frontiers in Pharmacology (2019).

Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials *


The clinical effectiveness of vitamin B12 and its active coenzyme form on diabetic neuropathy is uncertain. Therefore, we searched the English- and non-English-language literature on this topic by using MEDLINE (Ovid, PubMed), the Cochrane Controlled Trials Register, and related papers. We identified seven randomized controlled trials from June 1954 to July 2004 and reviewed them for the clinical effectiveness of vitamin B12 according to the following parameters: Measurement scales of somatic and autonomic symptoms or signs; vibrometer-detected thresholds of vibration perception; and, electrophysiologic measures such as nerve conduction velocities and evoked potentials. Three studies involved the use of vitamin B complex (including B12) as the active drug, and four used methylcobalamin. Two studies were of fairly good quality (Jadad score = 3/5), and five were of poor quality (Jadad score < or = 2/5). Both the vitamin B12 combination and pure methylcobalamin had beneficial effects on somatic symptoms, such as pain and paresthesia. In three studies, methylcobalamin therapy improved autonomic symptoms. Effects on vibration perception and electrophysiological measures were not consistent. With both the vitamin B12 combination and pure methylcobalamin, symptomatic relief was greater than changes in electrophysiological results. However, more high-quality, double-blind randomized controlled trials are needed to confirm the effects of vitamin B12 on diabetic neuropathy.

Source: Yu Sun, Mei-Shu Lai, and Chien-Jung Lu. “Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials” Acta Neurologica Taiwanica (2005): 14(2):48-54.

Pyridoxine (Vitamin B6)

The influence of pyridoxine in diabetic peripheral neuropathy*


To determine the role of pyridoxine in the treatment of diabetic peripheral neuropathy, 18 symptomatic diabetic patients were treated with vitamin B6 or placebo in a double-blind controlled study. Only one patient had a low plasma pyridoxal phosphate level at the start of the study. After 4 mo of treatment with pyridoxine hydrochloride (50 mg three times daily) 6 of 9 pyridoxine-treated and 4 of 9 placebo-treated patients noted significant relief from their neuropathic symptoms. There was no difference between the two groups with regard to fasting plasma glucose, motor nerve conduction velocity, or ophthalmologic examination at the beginning or at the conclusion of the study. Our results suggest that vitamin B6 deficiency is not a factor in the etiology of diabetic peripheral neuropathy. Furthermore, treating diabetic peripheral neuropathy with high dose vitamin B6 or placebo results in a similar frequency of symptomatic improvement.

Source: E. R. Levin, T. A. Hanscom, M. Fisher, W. A. Lauvstad, A. Lui, A. Ryan, D. Glockner, and S. R. Levin. “The influence of pyridoxine in diabetic peripheral neuropathy” Diabetes Care (1981): 4(6):606-9.

Pyridoxine deficiency and peripheral neuropathy associated with long-term phenelzine therapy*


A 51-year-old, nonalcoholic, nondiabetic woman with sensorimotor peripheral neuropathy and pyridoxine deficiency associated with long-term phenelzine therapy is described. Since phenelzine, like hydralazine and isoniazid, is a hydrazine capable of reducing pyridoxine levels in the rat, it is suggested that phenelzine, like hydralazine and isoniazid, may cause a pyridoxine-responsive peripheral neuropathy in humans.

Source: C. A. Heller, and P. A. Friedman. “Pyridoxine deficiency and peripheral neuropathy associated with long-term phenelzine therapy” The American Journal of Medicine (1983): 75(5):887-8.

Pyridoxine neuropathies. Review of the literature *


Daily needs of vitamin B6 are very low (2 mg per day) and widely covered by normal feeding. Pyridoxine deficiencies are exceptional (congenital metabolic abnormalities, drug or toxic-induced perturbations). First described in animal models, human cases of neuropathy had been encountered in the "megavitamin"-syndrome. They are confirmed by rare case-reports of very high doses given in toxic indication. Sensory peripheral neuropathies can also occur with lower doses taken over a long period of time.

Source: G. Dordain, and D. Deffond. “Pyridoxine neuropathies. Review of the literature” Therapie (1994): 49(4):333-7.

Benfotiamine (Thiamine/Vitamin B1 derivative)

Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study*


Aim: Efficacy and safety of benfotiamine in treatment of diabetic polyneuropathy.

Methods: Double blind, placebo-controlled, phase-III-study. 181 patients were screened. 165 patients with symmetrical, distal diabetic polyneuropathy were randomised to one of three treatment groups entering the wash-out phase and 133/124 patients were analysed in the ITT/PP analysis: Benfotiamine 600 mg per day (n=47/43), benfotiamine 300 mg per day (n=45/42) or placebo (n=41/39).

Results: After 6 weeks of treatment, the primary outcome parameter NSS (Neuropathy Symptom Score) differed significantly between the treatment groups (p=0.033) in the PP (per protocol) population. In the ITT (intention to treat) population, the improvement of NSS was slightly above significance (p=0.055). The TSS (Total Symptom Score) showed no significant differences after 6 weeks of treatment. The improvement was more pronounced at the higher benfotiamine dose and increased with treatment duration. In the TSS, best results were obtained for the symptom "pain". Treatment was well tolerated in all groups.

Conclusion: Benfotiamine may extend the treatment option for patients with diabetic polyneuropathy based on causal influence on impaired glucose metabolism. Further studies should confirm the positive experiences.

Source: H. Stracke, W. Gaus, U. Achenbach, K. Federlin, R. G. Bretzel. “Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study” Experimental and Clinical Endocrinology and Diabetes (2008): 116(10):600-5.

Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study) *


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.

Source: E. Haupt, H. Ledermann, W. Köpcke. “Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study)” International Journal of Clinical Pharmacology and Therapeutics (2005): 43(6):304.

Vitamin B for treating peripheral neuropathy *


Background: Vitamin B is frequently used for treating peripheral neuropathy, but its efficacy is not clear.

Objectives: The objective of this review was to assess the effects of vitamin B for treating generalised peripheral neuropathy.

Search strategy: We searched the Cochrane Neuromuscular Disease Group Trials Register (searched August 2005), MEDLINE (January 1966 to September 2005), EMBASE (January 1980 to September 2005), Philippine databases (searched September 2005) and reference lists of articles. We also contacted manufacturers and researchers in the field.

Selection criteria: Randomised and quasi-randomised trials where vitamin B was compared with placebo or another treatment in generalised peripheral neuropathy.

Data collection and analysis: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information.

Main results: Thirteen studies involving 741 participants with alcoholic or diabetic neuropathy were included. In the comparison of vitamin B with placebo, two small trials showed no significant short-term benefit in pain intensity while one of the trials showed a small significant benefit in vibration detection from oral benfotiamine, a derivative of thiamine. In the larger of two trials comparing different doses of vitamin B complex, there was some evidence that higher doses resulted in a significant short-term reduction in pain and improvement in paraesthesiae, in a composite outcome combining pain, temperature and vibration, and in a composite outcome combining pain, numbness and paraesthesiae. There was some evidence that vitamin B is less efficacious than alpha-lipoic acid, cilostazol or cytidine triphosphate in the short-term improvement of clinical and nerve conduction study outcomes but the trials were small. There were few minor adverse effects reported.

Authors' conclusions: There are only limited data in randomised trials testing the efficacy of vitamin B for treating peripheral neuropathy and the evidence is insufficient to determine whether vitamin B is beneficial or harmful. One small trial in alcoholic peripheral neuropathy reported slightly greater improvement in vibration perception threshold with oral benfotiamine for eight weeks than placebo. In another small study, a higher dose of oral vitamin B complex for four weeks was more efficacious than a lower dose in reducing symptoms and signs. Vitamin B administered by various routes for two to eight weeks was less efficacious than alpha-lipoic acid, cilostazol or cytidine triphosphate in short-term improvement of clinical and nerve conduction study outcomes. Vitamin B is generally well-tolerated.

Source: Cynthia D. Ang, Maria Jenelyn M. Alviar, Antonio L. Dans, Gwyneth Giselle P. Bautista-Velez, Maria Vanessa C. Villaruz-Sulit, Jennifer J. Tan, Homer U. Co, Maria Rhida M. Bautista, and Artemio A. Roxas. “Vitamin B for treating peripheral neuropathy” Cochrane Database of Systematic Reviews (2008): (3):CD004573.

Alpha-Lipoic Acid

Alpha-Lipoic Acid and Diabetic Neuropathy *


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.

Source: Natalia Vallianou, Angelos Evangelopoulos, and Pavlos Koutalas. “Alpha-Lipoic Acid and Diabetic Neuropathy” The Review of Diabetic Studies (2009): 6(4): 230–236.

Increasing bioavailability of (R)-alpha-lipoic acid to boost antioxidant activity in the treatment of neuropathic pain *


A-lipoic acid (a-LA) is a potent natural antioxidant because it has a broad spectrum of action towards a great many free radical species and boosts the endogenous antioxidant systems. Although, it is a multi-functional molecule, its pharmacokinetic characteristics pose restrictions to its use in the treatment of oxidative stress-dependent illnesses. Formulations that increase the bioavailability of a-LA have a better potential efficacy as adjuvants for the treatment of these conditions. This objective was achieved with a liquid formulation for oral use containing only R-aLA, the natural enantiomeric and most active form of a-lipoic acid. For the first time, the effects of this formulation were evaluated on neuropathic pain, a symptom caused by an increase in oxidative stress, regardless of the underlying cause. Neuropathic patients who have used this dietary supplement noticed an improvement in their quality of life and a significant reduction was observed in a number of certain descriptive pain parameters (intensity, burning, unpleasantness, superficial pain). Undoubtedly further, more in-depth, studies need to be conducted; however, this first investigation confirms the role of R-aLA as an antioxidant for the aetiological treatment of peripheral neuropathy. Increasing its plasma bioavailability even after a non-invasive administration through the oral route is a good starting point for proposing a valid adjuvant for the treatment of pain symptoms.

Source: Maglione E., Marrese C., Migliaro E., Marcuccio F., Panico C., Salvati C., Citro G., Roncagliolo F., Torello C., and Brufani M. “Increasing bioavailability of (R)-alpha-lipoic acid to boost antioxidant activity in the treatment of neuropathic pain” Europe PMC (2015): 86(3):226-233.

Protective effects of alpha-lipoic acid on experimental sciatic nerve crush injury in rats: assessed with functional, molecular and electromicroscopic analyses *


Aim: The present study aimed to demonstrate protective effects of alpha lipoic acid on experimental sciatic nerve crush injury model assessed with functional and electronmicroscopy analyses.

Methods: In this study, groups were Group 1; sham operated, Group 2; applied only sciatic nerve crush (Control), Group 3; Sciatic nerve crush + treated ALA 25 mg/kg (received orally) and Group 4; Sciatic nerve crush + treated ALA 50 mg/kg. Subsequently, sciatic nerves crush injury induced by forceps. At the second and fourth week, all animals were evaluated for sciatic functional index (SFI) and histomorphometric analyses with electronmicroscopy.

Results: The SFI was significantly increased for both ALA-treated groups 30 days post-injury compared with control groups. The elecronmicroscopy results demonstrated that the axon diameter, the myelin diameter, the area of regenerating axon and miyelin were better in the treatment group than in the control group. Also, ALA decreased IL-1β and Caspase 3 levels that increased in SNC group.

Conclusions: These results suggest that ALA neuroprotective agent for peripheral nerve injury (PNI) and promoted peripheral nerve regeneration via its anti-inflammatory and antiapoptotic effects.

Source: Recep Demir, Muhammed Yayla, Erol Akpinar, Murtaza Cakir, Cagatay Calikoglu, Lutfu Ozel, Gokhan Ozdemir, and Tolga Mercantepe. “Protective effects of alpha-lipoic acid on experimental sciatic nerve crush injury in rats: assessed with functional, molecular and electromicroscopic analyses” The International Journal of Neuroscience (2014): 124(12):935-43.

Oat Straw

Effect of Oat β-Glucan Intake on Glycaemic Control and Insulin Sensitivity of Diabetic Patients: A Meta-Analysis of Randomized Controlled Trials *


Many individual studies on oat β-glucan (OBG) confirmed its functionality in improving type 2 diabetes mellitus (T2DM), but disagreements were identified among those results. To derive a pooled estimate of these results, relevant articles, published before 5 September 2015, were collected from four electronic databases (Pubmed, Cochrane Library, Scopus, and Web of Science) and subjected to meta-analysis in the present work. In total, four articles, dealing with 350 T2DM patients combined, met the inclusion criteria. Compared to control, T2DM patients administrated OBG from 2.5 to 3.5 g/day for 3 to 8 weeks presented significantly lowered concentrations in fasting plasma glucose (FPG) by −0.52 (95% CI: −0.94, −0.10) mmol/L (p = 0.01) and glycosylated hemoglobin (HbA1c) by −0.21% (95% CI: −0.40, −0.02) (p = 0.03). However, OBG intake did not significantly lower the fasting plasma insulin (FPI) concentration. In conclusion, mediate-term OBG intake (3–8 weeks) favored the glycaemic control of T2DM patients but did not improve their insulin sensitivity. Regrettably, data upon the effects of long-term OBG intake on glycaemic control and insulin sensitivity were scarce, which is of much importance and should be addressed in future research.

Source: Xiao Li Shen, Tao Zhao, Yuanzhong Zhou, Xiuquan Shi, Yan Zou, and Guohua Zhao. “Effect of Oat β-Glucan Intake on Glycaemic Control and Insulin Sensitivity of Diabetic Patients: A Meta-Analysis of Randomized Controlled Trials” Nutrients (2016): 8(1): 39.

Protective Effects of Beta Glucan and Gliclazide on Brain Tissue and Sciatic Nerve of Diabetic Rats Induced by Streptozosin*

There have not been yet enough studies about effects of beta glucan and gliclazide on oxidative stress created by streptozotocin in the brain and sciatic nerve of diabetic rats. The aim of this paper was to investigate the antioxidant effects of gliclazide and beta glucan on oxidative stress and lipid peroxidation created by streptozotosin in brain and sciatic nerve. Total of 42 rats were divided into 6 groups including control, diabetic untreated (DM) (only STZ, diabetic), STZ (DM) + beta glucan, STZ (DM) + gliclazide, only beta glucan treated (no diabetic), and only gliclazide treated (no diabetic). The brain and sciatic nerve tissue samples were analyzed for malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), and paraoxonase (PON-1) levels. We found a significant increase in MDA, TOS, and OSI along with a reduction in TAS level, catalase, and PON-1 activities in brain and sciatic nerve of streptozotocin-induced diabetic rats. Also, this study shows that in terms of these parameters both gliclazide and beta glucan have a neuroprotective effect on the brain and sciatic nerve of the streptozotocin-induced diabetic rat. Our conclusion was that gliclazide and beta glucan have antioxidant effects on the brain and sciatic nerve of the streptozotocin-induced diabetic rat.

Source: Harun Alp, Sefer Varol, Muhammet Murat Celik, Murat Altas, Osman Evliyaoglu, Orhan Tokgoz, Mehmet Halis Tanrıverdi, and Ertugrul Uzar. “Protective Effects of Beta Glucan and Gliclazide on Brain Tissue and Sciatic Nerve of Diabetic Rats Induced by Streptozosin” Experimental Diabetes Research (2012): 2012: 230342.

The Metabolic Effects of Oats Intake in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis *


The present study aimed to comprehensively assess if oats intake is beneficial for diabetic patients. The literature search was conducted in PubMed database up to 23 August 2015. Fourteen controlled trials and two uncontrolled observational studies were included. Compared with the controls, oats intake significantly reduced the concentrations of glycosylated hemoglobin A1c (HbA1c) (MD, -0.42%; 95% CI, -0.61% to -0.23%), fasting blood glucose (FBG) (MD, -0.39 mmol/L; 95% CI, -0.58 to -0.19 mmol/L), total cholesterol (TC) (MD, -0.49 mmol/L; 95% CI, -0.86 to -0.12 mmol/L), low-density lipoprotein cholesterol (LDL-C) (MD, -0.29 mmol/L; 95% CI, -0.48 to -0.09 mmol/L). Oatmeal significantly reduced the acute postprandial glucose and insulin responses compared with the control meal. The present study has revealed a beneficial effect of oats intake on glucose control and lipid profiles in type 2 diabetic patients. Further investigations of oats intake in patients with type 1 diabetes and the safety of oats consumption are required.

Source: Qingtao Hou, Yun Li, Ling Li, Gaiping Cheng, Xin Sun, Sheyu Li, Haoming Tian. “The Metabolic Effects of Oats Intake in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis” Nutrients (2015): 7(12):10369-87.


Passiflora incarnata attenuation of neuropathic allodynia and vulvodynia apropos GABA-ergic and opioidergic antinociceptive and behavioural mechanisms *

Abstract Background: Passiflora incarnata is widely used as an anxiolytic and sedative due to its putative GABAergic properties. Passiflora incarnata L. methanolic extract (PI-ME) was evaluated in an animal model of streptozotocin-induced diabetic neuropathic allodynia and vulvodynia in rats along with antinociceptive, anxiolytic and sedative activities in mice in order to examine possible underlying mechanisms.

Methods: PI-ME was tested preliminary for qualitative phytochemical analysis and then quantitatively by proximate and GC-MS analysis. The antinociceptive property was evaluated using the abdominal constriction assay and hot plate test. The anxiolytic activity was performed in a staircase model and sedative activity in an open field test. The antagonistic activities were evaluated using naloxone and/or pentylenetetrazole (PTZ). PI-ME was evaluated for prospective anti-allodynic and anti-vulvodynic properties in a rat model of streptozotocin induced neuropathic pain using the static and dynamic testing paradigms of mechanical allodynia and vulvodynia.

Results: GC-MS analysis revealed that PI-ME contained predominant quantities of oleamide (9-octadecenamide), palmitic acid (hexadecanoic acid) and 3-hydroxy-dodecanoic acid, among other active constituents. In the abdominal constriction assay and hot plate test, PI-ME produced dose dependant, naloxone and pentylenetetrazole reversible antinociception suggesting an involvement of opioidergic and GABAergic mechanisms. In the stair case test, PI-ME at 200 mg/kg increased the number of steps climbed while at 600 mg/kg a significant decrease was observed. The rearing incidence was diminished by PI-ME at all tested doses and in the open field test, PI-ME decreased locomotor activity to an extent that was analagous to diazepam. The effects of PI-ME were antagonized by PTZ in both the staircase and open field tests implicating GABAergic mechanisms in its anxiolytic and sedative activities. In the streptozotocin-induced neuropathic nociceptive model, PI-ME (200 and 300 mg/kg) exhibited static and dynamic anti-allodynic effects exemplified by an increase in paw withdrawal threshold and paw withdrawal latency. PI-ME relieved only the dynamic component of vulvodynia by increasing flinching response latency.

Conclusions: These findings suggest that Passiflora incarnata might be useful for treating neuropathic pain. The antinociceptive and behavioural findings inferring that its activity may stem from underlying opioidergic and GABAergic mechanisms though a potential oleamide-sourced cannabimimetic involvement is also discussed.

Source: Urooj Aman, Fazal Subhan,corresponding author Muhammad Shahid, Shehla Akbar, Nisar Ahmad, Gowhar Ali, Khwaja Fawad, and Robert D. E. Sewell. “Passiflora incarnata attenuation of neuropathic allodynia and vulvodynia apropos GABA-ergic and opioidergic antinociceptive and behavioural mechanisms” BMC complimentary Medicine and Therapies (2016): 16: 77.

Neural plasticity after peripheral nerve injury and regeneration *


Injuries to the peripheral nerves result in partial or total loss of motor, sensory and autonomic functions conveyed by the lesioned nerves to the denervated segments of the body, due to the interruption of axons continuity, degeneration of nerve fibers distal to the lesion and eventual death of axotomized neurons. Injuries to the peripheral nervous system may thus result in considerable disability. After axotomy, neuronal phenotype switches from a transmitter to a regenerative state, inducing the down- and up-regulation of numerous cellular components as well as the synthesis de novo of some molecules normally not expressed in adult neurons. These changes in gene expression activate and regulate the pathways responsible for neuronal survival and axonal regeneration. Functional deficits caused by nerve injuries can be compensated by three neural mechanisms: the reinnervation of denervated targets by regeneration of injured axons, the reinnervation by collateral branching of undamaged axons, and the remodeling of nervous system circuitry related to the lost functions. Plasticity of central connections may compensate functionally for the lack of specificity in target reinnervation; plasticity in human has, however, limited effects on disturbed sensory localization or fine motor control after injuries, and may even result in maladaptive changes, such as neuropathic pain, hyperreflexia and dystonia. Recent research has uncovered that peripheral nerve injuries induce a concurrent cascade of events, at the systemic, cellular and molecular levels, initiated by the nerve injury and progressing throughout plastic changes at the spinal cord, brainstem relay nuclei, thalamus and brain cortex. Mechanisms for these changes are ubiquitous in central substrates and include neurochemical changes, functional alterations of excitatory and inhibitory connections, atrophy and degeneration of normal substrates, sprouting of new connections, and reorganization of somatosensory and motor maps. An important direction for ongoing research is the development of therapeutic strategies that enhance axonal regeneration, promote selective target reinnervation, but are also able to modulate central nervous system reorganization, amplifying those positive adaptive changes that help to improve functional recovery but also diminishing undesirable consequences.

Source: X. Navarro, Meritxell Vivó, and Antoni Valero-Cabré. “Neural plasticity after peripheral nerve injury and regeneration” Progress in Neurobiology (2007): 82(4):163-201.

Passiflora incarnata L. (Passionflower) extracts elicit GABA currents in hippocampal neurons in vitro, and show anxiogenic and anticonvulsant effects in vivo, varying with extraction method *


Potential mechanisms of Passiflora incarnata extracts and the effect of extraction methods on ingredients and biological effects were explored. Using the same batch of plant material, total flavonoid yields as measured by high-performance liquid chromatography coupled to diode array detection (HPLC-DAD) increased substantially with hot versus cold extraction methods. Whole Passiflora extract induced prominent, dose-dependent direct GABA(A) currents in hippocampal slices, but the expected modulation of synaptic GABA(A) currents was not seen. GABA was found to be a prominent ingredient of Passiflora extract, and GABA currents were absent when amino acids were removed from the extract. Five different extracts, prepared from a single batch of Passiflora incarnata, were administered to CF-1 mice for 1 week in their drinking water prior to evaluation of their behavioral effects. Anticonvulsant effects against PTZ-induced seizures were seen in mice that received 2 of the 5 Passiflora extracts. Instead of the anxiolytic effects described by others, anxiogenic effects in the elevated plus maze were seen in mice receiving any of the 5 Passiflora extracts.

Source: Siegward-M. Elsas, D.J. Rossi, Jacob Raber, and Gianetta White “Passiflora incarnata L. (Passionflower) extracts elicit GABA currents in hippocampal neurons in vitro, and show anxiogenic and anticonvulsant effects in vivo, varying with extraction method” Phytomedicine: International Journal of Phytotherapy and Phytopharmacology (2010): 17(12):940-9.

Baical Skullcap

Neuroprotective and Cognitive Enhancement Potentials of Baicalin: A Review *


Neurodegenerative diseases are a heterogeneous group of disorders that are characterized by the gradual loss of neurons. The development of effective neuroprotective agents to prevent and control neurodegenerative diseases is specifically important. Recently, there has been an increasing interest in selecting flavonoid compounds as potential neuroprotective agents, owing to their high effectiveness with low side effects. Baicalin is one of the important flavonoid compounds, which is mainly isolated from the root of Scutellaria baicalensis Georgi (an important Chinese medicinal herb). In recent years, a number of studies have shown that baicalin has a potent neuroprotective effect in various in vitro and in vivo models of neuronal injury. In particular, baicalin effectively prevents neurodegenerative diseases through various pharmacological mechanisms, including antioxidative stress, anti-excitotoxicity, anti-apoptotic, anti-inflammatory, stimulating neurogenesis, promoting the expression of neuronal protective factors, etc. This review mainly focuses on the neuroprotective and cognitive enhancement effects of baicalin. The aim of the present review is to compile all information in relation to the neuroprotective and cognitive enhancement effects of baicalin and its molecular mechanisms of action in various in vitro and in vivo experimental models.

Source: Kandhasamy Sowndhararajan, Ponnuvel Deepa, Minju Kim, Se Jin Park, and Songmun Kim. “Neuroprotective and Cognitive Enhancement Potentials of Baicalin: A Review” Brain Sciences (2018): 8(6): 104.

Effects of baicalin on diabetic neuropathic pain involving transient receptor potential vanilloid 1 in the dorsal root ganglia of rats *


Diabetic peripheral neuropathy is the most common complication of diabetes mellitus and leads to sensory symptoms, including diabetic neuropathic pain (DNP). DNP is a major public health problem because it has a considerable impact on life quality of diabetes mellitus patients. Therefore, development of novel effective analgesics for DNP relief and treatment is warranted. Transient receptor potential vanilloid 1 (TRPV1) has a crucial role in nociceptive transmission under pathological forms of pain. Baicalin is a flavonoid compound extracted from a medicinal herb, Huang Qin, it possesses antioxidant properties and has an analgesic effect on nitroglycerin-induced migraine in rats and neuropathic pain in spinal nerve ligation rats. However, the effects of baicalin on DNP are unclear. Therefore, the aim of this study is to examine the effects of baicalin on DNP. Our data show that a single dose of baicalin (40 µg/kg) had a transient analgesic effect on streptozotocin (STZ)-induced DNP rats. Moreover, cumulative injection of baicalin prevented the development of STZ-induced DNP in rats in a dose-dependent manner. In addition, baicalin dose-dependently suppressed the expression of TRPV1 in dorsal root ganglia of STZ-induced DNP rats. Therefore, the analgesic role of baicalin in DNP probably occurred through TRPV1. Baicalin may play an important analgesic role in DNP and might serve as a potential compound in clinical treatment and prevention of DNP.

Source: Ping Li, Dong-Lin Xiong, Wu-Ping Sun, Shi-Yuan Xu. “Effects of baicalin on diabetic neuropathic pain involving transient receptor potential vanilloid 1 in the dorsal root ganglia of rats” Neuroreport(2018): 29(17):1492-1498.

A Novel Analgesic Isolated from a Traditional Chinese Medicine *


Background: Current pain management is limited, in particular, with regard to chronic pain. In an attempt to discover novel analgesics, we combined the approach developed to characterize traditional Chinese medicine (TCM), as part of the "herbalome" project, with the reverse pharmacology approach aimed at discovering new endogenous transmitters and hormones.

Results: In a plant used for centuries for its analgesic properties, we identify a compound, dehydrocorybulbine (DHCB), that is effective at alleviating thermally induced acute pain. We synthesize DHCB and show that it displays moderate dopamine receptor antagonist activities. By using selective pharmacological compounds and dopamine receptor knockout (KO) mice, we show that DHCB antinociceptive effect is primarily due to its interaction with D2 receptors, at least at low doses. We further show that DHCB is effective against inflammatory pain and injury-induced neuropathic pain and furthermore causes no antinociceptive tolerance.

Conclusions: Our study casts DHCB as a different type of analgesic compound and as a promising lead in pain management.

Source: Yan Zhang, Chaoran Wang, Lien Wang, Gregory Scott Parks, Xiuli Zhang, Zhimou Guo, Yanxiong Ke, Kang-Wu Li, Mi Kyeong Kim, Benjamin Vo, Emiliana Borrelli, Guangbo Ge, Ling Yang, Zhiwei Wang, M. Julia Garcia-Fuster, Z. David Luo, Xinmiao Liang, Olivier Civelli. “A Novel Analgesic Isolated from a Traditional Chinese Medicine.” Current Biology, (2014): 24(2):117-123.