Benfotiamine and Polyneuropathy
Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study.
Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG, Exp Clin Endocrinol Diabetes. 2008 Nov;116(10): 600-5.
ABSTRACT: 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.
Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP Study).
Haupt E, Ledermann H, Köpcke W. Int J Clin Pharmacol Ther. 2005 Feb;43(2):71-7.
ABSTRACT: 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.  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.
Benfotiamine in the treatment of alcoholic polyneuropathy: an 8- week randomized controlled study (BAP study).
Woelk H, Lehrl S, Bitsch R, Köpcke W. Alcohol Alcohol. 1998 Nov-Dec;33(6):631-8.
ABSTRACT: A three-armed, randomized, multicentre, placebo-controlled double-blind study was used to examine the efficacy of benfotiamine vs a combination containing benfotiamine and vitamins B6 and B12 in outpatients with severe symptoms of alcoholic polyneuropathy (Benfotiamine in treatment of Alcoholic Polyneuropathy. BAP I). The study period was 8 weeks and 84 patients fulfilled all the prerequisite criteria and completed the study as planned. Benfotiamine led to significant improvement of alcoholic polyneuropathy. Vibration perception (measured at the tip of the great toe) significantly improved in the course of the study, as did motor function, and the overall score reflecting the entire range of symptoms of alcoholic polyneuropathy. A tendency toward improvement was evident for pain and co-ordination; no therapy-specific adverse effects were seen.
Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy.
Winkler G, Pál B, Nagybéganyi E, Ory I, Porochnavec M, Kempler P. Arzneimittelforschung. 1999 Mar;49(3):220-4.
ABSTRACT: 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 other 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.
A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy.
Stracke H, Lindemann A, Federlin K. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6.
ABSTRACT: 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.
Benfotiamine, Thiamine and Diabetic Complications
The pathobiology of diabetic complications: a unifying mechanism.
Brownlee M.: Diabetes. 2005 Jun;54(6):1615-25.
The multifaceted therapeutic potential of benfotiamine.
Balakumar P1, Rohilla A, Krishan P, Solairaj P, Thangathirupathi A., Pharmacol Res. 2010 Jun;61(6):482-8. doi: 10.1016/j.phrs.2010.02.008. Epub 2010 Feb 25.
ABSTRACT: Thiamine, known as vitamin B(1), plays an essential role in energy metabolism. Benfotiamine (S-benzoylthiamine O-monophoshate) is a synthetic S-acyl derivative of thiamine. Once absorbed, benfotiamine is dephosphorylated by ecto-alkaline phosphatase to lipid-soluble S-benzoylthiamine. Transketolase is an enzyme that directs the precursors of advanced glycation end products (AGEs) to pentose phosphate pathway. Benfotiamine administration increases the levels of intracellular thiamine diphosphate, a cofactor necessary for the activation transketolase, resulting in the reduction of tissue level of AGEs. The elevated level of AGEs has been implicated in the induction and progression of diabetes-associated complications. Chronic hyperglycemia accelerates the reaction between glucose and proteins leading to the formation of AGEs, which form irreversible cross-links with many macromolecules such as collagen. In diabetes, AGEs accumulate in tissues at an accelerated rate. Experimental studies have elucidated that binding of AGEs to their specific receptors (RAGE) activates mainly monocytes and endothelial cells and consequently induces various inflammatory events. Moreover, AGEs exaggerate the status of oxidative stress in diabetes that may additionally contribute to functional changes in vascular tone control observed in diabetes. The anti-AGE property of benfotiamine certainly makes it effective for the treatment of diabetic neuropathy, nephropathy and retinopathy. Interestingly, few recent studies demonstrated additional non-AGE-dependent pharmacological actions of benfotiamine. The present review critically analyzed the multifaceted therapeutic potential of benfotiamine.
Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy.
Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Nat Med. 2003 Mar;9(3):294-9.
ABSTRACT: Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-kappaB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-kappaB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.
The potential role of thiamine (vitamin B1) in diabetic complications.
Thornalley, PJ; Curr Diabetes Rev. 2005 Aug; 1(3): 287-98.
ABSTRACT: Accumulation of triose phosphates arising from high cytosolic glucose concentrations in hyperglycemia is one likely or potential trigger for biochemical dysfunction leading to the development of diabetic complications. This may be prevented by disposal of excess triose phosphates via the reductive pentose phosphate pathway. This pathway is impaired in experimental and clinical diabetes by mild thiamine deficiency. The expression and activity of the thiamine-dependent enzyme, transketolase - the pace making enzyme of the reductive pentose phosphate pathway, is consequently decreased. Correction of thiamine deficiency in experimental diabetes by high dose therapy with thiamine and the thiamine monophosphate prodrug, Benfotiamine, restores disposal of triose phosphates by the reductive pentose phosphate pathway in hyperglycemia. This prevented multiple mechanisms of biochemical dysfunction: activation of protein kinase C, activation of the hexosamine pathway, increased glycation and oxidative stress. Consequently, the development of incipient diabetic nephropathy, neuropathy and retinopathy were prevented. Both thiamine and Benfotiamine produced other remarkable effects in experimental diabetes: marked reversals of increased diuresis and glucosuria without change in glycemic status. High dose thiamine also corrected dyslipidemia in experimental diabetes - normalizing cholesterol and triglycerides. Dysfunction of bgr-cells and impaired glucose tolerance in thiamine deficiency and suggestion of a link of impaired glucose tolerance with dietary thiamine indicates that thiamine therapy may have a future role in prevention of type 2 diabetes. More immediately, given the emerging multiple benefits of thiamine repletion, even mild thiamine deficiency in diabetes should be avoided and thiamine supplementation to high dose should be considered as adjunct nutritional therapy to prevent dyslipidemia and the development of vascular complications in clinical diabetes.
High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease.
Thornalley PJ, Babaei-Jadidi R, Al Ali H, Rabbani N, Antonysunil A, Larkin J, Ahmed A, Rayman G, Bodmer CW., Diabetologia. 2007 Oct; 50(10): 2164-70.
ABSTRACT: AIMS/HYPOTHESIS: To assess thiamine status by analysis of plasma, erythrocytes and urine in type 1 and type 2 diabetic patients and links to markers of vascular dysfunction. METHODS: Diabetic patients (26 type 1 and 48 type 2) with and without microalbuminuria and 20 normal healthy control volunteers were recruited. Erythrocyte activity of transketolase, the concentrations of thiamine and related phosphorylated metabolites in plasma, erythrocytes and urine, and markers of metabolic control and vascular dysfunction were determined. RESULTS: Plasma thiamine concentration was decreased 76% in type 1 diabetic patients and 75% in type 2 diabetic patients: normal volunteers 64.1 (95% CI 58.5–69.7) nmol/l, type 1 diabetes 15.3 (95% CI 11.5–19.1) nmol/l, p < 0.001, and type 2 diabetes 16.3 (95% CI 13.0–9.6) nmol/l, p < 0.001. Renal clearance of thiamine was increased 24-fold in type 1 diabetic patients and 16-fold in type 2 diabetic patients. Plasma thiamine concentration correlated negatively with renal clearance of thiamine (r = −0.531, p < 0.001) and fractional excretion of thiamine (r = −0.616, p < 0.001). Erythrocyte transketolase activity correlated negatively with urinary albumin excretion (r = −0.232, p < 0.05). Thiamine transporter protein contents of erythrocyte membranes of type 1 and type 2 diabetic patients were increased. Plasma thiamine concentration and urinary excretion of thiamine correlated negatively with soluble vascular adhesion molecule-1 (r = -0.246, p < 0.05, and −0.311, p < 0.01, respectively). CONCULUSIONS/INTERPRETATION: Low plasma thiamine concentration is prevalent in patients with type 1 and type 2 diabetes, associated with increased thiamine clearance. The conventional assessment of thiamine status was masked by increased thiamine transporter content of erythrocytes.
Thiamine deficiency in diabetes mellitus and the impact of thiamine replacement on glucose metabolism and vascular disease.
Page GL, Laight D, Cummings MH. Int J Clin Pract. 2011 Jun;65(6):684-90.
ABSTRACT: Despite the targeting of traditional risk factors for cardiovascular disease, disease burden has not been completely eliminated. Thiamine is an essential cofactor in carbohydrate metabolism and individuals with diabetes are thiamine deficient. The pathophysiology of recognised complications of thiamine deficiency is similar to that underlying atherosclerosis and the metabolic syndrome, namely oxidative stress, inflammation and endothelial dysfunction. This review examines the mechanisms by which thiamine deficiency occurs in individuals with diabetes, how this deficiency leads to hyperglycaemic-induced damage, and the effect of thiamine replacement on vascular disease, endothelial function and oxidative stress. Thiamine administration can prevent the formation of harmful by-products of glucose metabolism, reduce oxidative stress and improve endothelial function. The potential benefit of long-term replacement in those with diabetes is not yet known but may reduce cardiovascular risk and angiopathic complications.
Benfotiamine, Thiamine and Alzheimer’s Disease
Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice.
Pan, et al., Brain. 2010 May;133(Pt 5):1342-51. doi: 10.1093/brain/awq069. Epub 2010 Apr 12.
ABSTRACT: Reduction of glucose metabolism in brain is one of the main features of Alzheimer's disease. Thiamine (vitamin B1)-dependent processes are critical in glucose metabolism and have been found to be impaired in brains from patients with Alzheimer's disease. However, thiamine treatment exerts little beneficial effect in these patients. Here, we tested the effect of benfotiamine, a thiamine derivative with better bioavailability than thiamine, on cognitive impairment and pathology alterations in a mouse model of Alzheimer's disease, the amyloid precursor protein/presenilin-1 transgenic mouse. We show that after a chronic 8 week treatment, benfotiamine dose-dependently enhanced the spatial memory of amyloid precursor protein/presenilin-1 mice in the Morris water maze test. Furthermore, benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains. Unexpectedly, these effects were not mimicked by another lipophilic thiamine derivative, fursultiamine, although both benfotiamine and fursultiamine were effective in increasing the levels of free thiamine in the brain. Most notably, benfotiamine, but not fursultiamine, significantly elevated the phosphorylation level of glycogen synthase kinase-3alpha and -3beta, and reduced their enzymatic activities in the amyloid precursor protein/presenilin-1 transgenic brain. Therefore, in the animal Alzheimer's disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms, which are likely to include the suppression of glycogen synthase kinase-3 activities. These results suggest that, unlike many other thiamine-related drugs, benfotiamine may be beneficial for clinical Alzheimer's disease treatment.
Abnormal thiamine-dependent processes in Alzheimer's Disease. Lessons from diabetes.
Mol Cell Neurosci. 2013 Jul;55:17-25. doi: 10.1016/j.mcn.2012.09.001. Epub 2012 Sep 13 Gibson GE1, Hirsch JA, Cirio RT, Jordan BD, Fonzetti P, Elder J.
ABSTRACT: Reduced glucose metabolism is an invariant feature of Alzheimer's Disease (AD) and an outstanding biomarker of disease progression. Glucose metabolism may be an attractive therapeutic target, whether the decline initiates AD pathophysiology or is a critical component of a cascade. The cause of cerebral regional glucose hypometabolism remains unclear. Thiamine-dependent processes are critical in glucose metabolism and are diminished in brains of AD patients at autopsy. Further, the reductions in thiamine-dependent processes are highly correlated to the decline in clinical dementia rating scales. In animal models, thiamine deficiency exacerbates plaque formation, promotes phosphorylation of tau and impairs memory. In contrast, treatment of mouse models of AD with the thiamine derivative benfotiamine diminishes plaques, decreases phosphorylation of tau and reverses memory deficits. Diabetes predisposes to AD, which suggests they may share some common mechanisms. Benfotiamine diminishes peripheral neuropathy in diabetic humans and animals. In diabetes, benfotiamine induces key thiamine-dependent enzymes of the pentose shunt to reduce accumulation of toxic metabolites including advanced glycation end products (AGE). Related mechanisms may lead to reversal of plaque formation by benfotiamine in animals. If so, the use of benfotiamine could provide a safe intervention to reverse biological and clinical processes of AD progression. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'.
Alterations of Thiamine Phosphorylation and of Thiamine- Dependent Enzymes in Alzheimer's Disease.
Maryse Herouxl, et al., Metabolic Brain Disease, Vol. 11, No. 1, 1996
There is a growing body of evidence to suggest that thiamine neurochemistry is disrupted in Alzheimer's Disease (AD). Studies in autopsied brain tissue from neuropathologically proven AD patients reveal significantly reduced activities of the thiamine phosphate dephosphorylating enzymes thiamine diphosphatase (TDPase) and thiamine monophosphatase (TMPase) as well as the thiamine diphosphate-dependent enzymes, pyruvate dehydrogenase complex, a-ketoglutarate dehydrogenase (aKGDH) and transketolase. Reductions in enzyme activities are present both in affected areas of AD brain as well as in relatively well conserved tissue. Decreased TDP concentrations and concomitantly increased TMP in autopsied brain tissue from AD patients and in CSF from patients with Dementia of the Alzheimer Type suggests that CNS thiamine phosphorylation-dephosphorylation mechanisms are disrupted in AD . aKGDH is a rate- limiting enzyme for cerebral glucose utilization and decreases in its activity are associated with lactic acidosis, cerebral energy failure and neuronal cell loss . Deficiencies of TDP-related metabolic processes could therefore participate in neuronal cell death mechanisms in AD.
Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers.
Rieck J, Halkin H, Almog S, Seligman H, Lubetsky A, Olchovsky D, Ezra D.
J Lab Clin Med. 1999 Sep;134(3):238-43.
ABSTRACT: Prolonged furosemide treatment is associated with urinary loss of thiamine and thiamine deficiency in some patients with congestive heart failure and low dietary thiamine intake. In the rat, diuretic-induced thiamine urinary loss is solely dependent on increased diuresis and is unrelated to the type of diuretic used. We studied the effects of single intravenous doses of furosemide (1, 3, and 10 mg) and of normal saline infusion (750 mL) on urinary thiamine excretion in 6 volunteers. Over a 6-hour period, furosemide induced dose-dependent increases in urine flow and sodium excretion rates (mean +/- SD), from 51 +/- 17 mL/h at baseline to 89 +/- 29 mL/h, 110 +/- 38 mL/h, and 183 +/- 58 mL/h (F = 10.4, P < .002) and from 5.1 +/- 2.3 mmol/h to 9.4 +/- 6.8 mmol/h, 12.1 +/- 2.6 mmol/h, and 20.9 +/- 10.6 mmol/h (F = 6.3, P < .005) for the three doses, respectively (104 +/- 35 mL/h and 13.0 +/- 6.2 mmol/h for the saline infusion). During this period the thiamine excretion rate doubled from baseline levels (mean of four 24-hour periods before the diuretic interventions) of 6.4 +/- 5.1 nmol/h to 11.6 +/- 8.2 nmol/h (F = 5.03, P < .01, for all four interventions, no difference being found between them), then returning over the following 18 hours to 6.1 +/- 3.9 nmol/h. The thiamine excretion rate was correlated with the urine flow rate (r = 0.54, P < .001), with no further effect of the type of intervention or sodium excretion rate. These findings complement our previous results in animals and indicate that sustained diuresis of >100 mL/h induces a nonspecific but significant increase in urinary loss of thiamine in human subjects. Thiamine supplements should be considered in patients undergoing sustained diuresis, when dietary deficiency may be present.
Mechanisms of thiamin deficiency in chronic alcoholism.
Hoyumpa AM Jr.; Am J Clin Nutr. 1980 Dec;33(12):2750-61.
ABSTRACT: In the United States and other developed countries thiamin deficiency is often related to chronic alcoholism. A number of mechanisms may be involved in the pathogenesis of thiamin deficiency in the alcoholic population. An important cause is inadequate intake of thiamin. Moreover, there may be decreased conversion of thiamin to the active coenzyme, reduced hepatic storage of the vitamin in patients with fatty metamorphosis, ethanol inhibition of intestinal thiamin transport, and impaired thiamin absorption secondary to other states of nutritional deficiency. The present discussion focuses on the mechanism of ethanol-related thiamin malabsorption. Under normal conditions thiamin transport in animals and humans is biphasic. At low or physiological thiamin concentrations, transport is a saturable, carrier-mediated, active process; but at higher concentrations, the transport of thiamin is predominantly passive. Ethanol reduces the rate of intestinal absorption and the net transmural flux of thiamin. Furthermore, ethanol inhibits only the active and not the passive component of thiamin transport by impeding the cellular exit of thiamin across the basolateral or serosal membrane. The impairment of thiamin movement out of the enterocyte correlates with a fall in the activity of Na-K ATPase. Bound to the basolateral membrane, Na-K ATPase is believed to be involved in the kinetics of active transport. Ethanol also increases the fluidity of enterocyte brush border and basolateral membranes. Since ethanol increases membrane fluidity it is possible that tahe impairment of thiamin transport and the diminution of Na-K ATPase activity may be related, at least partly, to a physical perturbation of the enterocyte membrane.
Axonal degeneration in beriberi neuropathy.
Takahashi K, Nakamura H; Arch Neurol. 1976 Dec;33(12):836-41.
ABSTRACT: Ultrastructural and teased-fiber studies were carried out on the sural nerves of nine patients with beriberi neuropathy Axonal degeneration was the most prominent feature, and large myelinated fibers were more affected than unmyelinated ones. An unusual change with accumulation of flattened sacs or tubuli was recognized in the axoplasm of myelinated fibers of untreated patients. Active regeneration was extensive in patients receiving vitamin B. Segmental demyelination, remyelination, and early onion bulbs were scarce in patients with a long and relapsing course before treatment.
Mitochondrial Dysfunction and Polyneuropathy
Mitochondrial dynamics and peripheral neuropathy.
Baloh RH. Neuroscientist. 2008 Feb;14(1):12-8.
ABSTRACT: Peripheral neuropathy is perhaps the archetypal disease of axonal degeneration, characteristically involving degeneration of the longest axons in the body. Evidence from both inherited and acquired forms of peripheral neuropathy strongly supports that the primary pathology is in the axons themselves and points to disruption of axonal transport as an important disease mechanism. Recent studies in human genetics have further identified abnormalities in mitochondrial dynamics--the fusion, fission, and movement of mitochondria--as a player in the pathogenesis of inherited peripheral neuropathy. This review provides an update on the mechanisms of mitochondrial trafficking in axons and the emerging relationship between the disruption of mitochondrial dynamics and axonal degeneration. Evidence suggests mitochondria are a "critical cargo" whose transport is necessary for proper axonal and synaptic function. Importantly, understanding the regulation of mitochondrial movement and the consequences of decreased axonal mitochondrial function may define new paths for therapeutic agents in peripheral neuropathy and other neurodegenerative diseases.
Mechanism of mitochondrial dysfunction in diabetic sensory neuropathy.
Fernyhough P, Huang TJ, Verkhratsky A., J Peripher Nerv Syst. 2003 Dec;8(4):227-35.
ABSTRACT: Symmetrical sensory polyneuropathy, the most common form of diabetic neuropathy in humans, is associated with a spectrum of structural changes in peripheral nerve that includes axonal degeneration, paranodal demyelination, and loss of myelinated fibers--the latter probably the result of a dying-back of distal axons. Mitochondrial dysfunction has recently been proposed as an etiological factor in this degenerative disease of the peripheral nervous system. Lack of neurotrophic support has been proposed as a contributing factor in the etiology of diabetic neuropathy based on studies in animal models of Type I diabetes. We have recently demonstrated that insulin and neurotrophin-3 (NT-3) modulate mitochondrial membrane potential in cultured adult sensory neurons. We therefore tested the hypothesis that diabetes-induced mitochondrial dysfunction is caused by impairments in neurotrophic support. We have used real-time fluorescence video microscopy to analyze mitochondrial membrane potential in cultured adult sensory neurons isolated from normal and diabetic rats. Diabetes caused a significant loss of mitochondrial membrane potential in all sub-populations of sensory neurons which can be prevented by in vivo treatment with insulin or NT-3. The mechanism of insulin and NT-3-dependent modulation of mitochondrial membrane potential involves the activation of the phosphoinositide 3 kinase (PI 3 kinase) pathway. Downstream targets of PI 3 kinase, such as Akt and the transcription factor cAMP response element-binding protein (CREB), are activated by insulin and NT-3 and regulate sensory neuron gene expression. These alterations in gene expression modulate critical components of metabolite pathways and the electron transport chain associated with the neuronal mitochondrion. Our results show that in adult sensory neurons, treatment with insulin can elevate the input of reducing equivalents into the mitochondrial electron transport chain, which leads to greater mitochondrial membrane polarization and enhanced ATP synthesis.
Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction.
Flatters SJ, Bennett GJ.; Pain. 2006 Jun;122(3):245-57.
ABSTRACT: Paclitaxel chemotherapy frequently induces neuropathic pain during and often persisting after therapy. The mechanisms responsible for this pain are unknown. Using a rat model of paclitaxel-induced painful peripheral neuropathy, we have performed studies to search for peripheral nerve pathology. Paclitaxel-induced mechano-allodynia and mechano-hyperalgesia were evident after a short delay, peaked at day 27 and finally resolved on day 155. Paclitaxel- and vehicle-treated rats were perfused on days 7, 27 and 160. Portions of saphenous nerves were processed for electron microscopy. There was no evidence of paclitaxel-induced degeneration or regeneration as myelin structure was normal and the number/density of myelinated axons and C-fibres was unaltered by paclitaxel treatment at any time point. In addition, the prevalence of ATF3-positive dorsal root ganglia cells was normal in paclitaxel-treated animals. With one exception, at day 160 in myelinated axons, total microtubule densities were also unaffected by paclitaxel both in C-fibres and myelinated axons. C-fibres were significantly swollen following paclitaxel at days 7 and 27 compared to vehicle. The most striking finding was significant increases in the prevalence of atypical (swollen and vacuolated) mitochondria in both C-fibres (1.6- to 2.3-fold) and myelinated axons (2.4- to 2.6-fold) of paclitaxel-treated nerves at days 7 and 27. Comparable to the pain behaviour, these mitochondrial changes had resolved by day 160. Our data do not support a causal role for axonal degeneration or dysfunction of axonal microtubules in paclitaxel-induced pain. Instead, our data suggest that a paclitaxel-induced abnormality in axonal mitochondria of sensory nerves contributes to paclitaxel-induced pain.
Mitotoxicity in distal symmetrical sensory peripheral neuropathies.
Gary J. Bennett, Timothy Doyle and Daniela Salvemini, Nat. Rev. Neurol. 10, 326–336 (2014); published online 20 May 2014; corrected online 1 July 2014; doi:10.1038/nrneurol.2014.77
ABSTRACT: Chronic distal symmetrical sensory peripheral neuropathy is a common neurological complication of cancer chemotherapy, HIV treatment and diabetes. Although aetiology-specific differences in presentation are evident, the clinical signs and symptoms of these neuropathies are clearly similar. Data from animal models
of neuropathic pain suggest that the similarities have a common cause: mitochondrial dysfunction in primary afferent sensory neurons. Mitochondrial dysfunction is caused by mitotoxic effects of cancer chemotherapeutic drugs of several chemical classes, HIV-associated viral proteins, and nucleoside reverse transcriptase inhibitor treatment, as well as the (possibly both direct and indirect) effects of excess glucose. The mitochondrial
injury results in a chronic neuronal energy deficit, which gives rise to spontaneous nerve impulses and a compartmental neuronal degeneration that is first apparent in the terminal receptor arbor—that is, intraepidermal nerve fibres—of cutaneous afferent neurons. Preliminary data suggest that drugs that prevent mitochondrial injury or improve mitochondrial function could be useful in the treatment of these conditions.
Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy.
Lehmann HC, Chen W, Borzan J, Mankowski JL, Höke A. Ann Neurol. 2011 Jan;69(1):100-10.
ABSTRACT: OBJECTIVE: Accumulation of mitochondrial DNA (mtDNA) damage has been associated with aging and abnormal oxidative metabolism. We hypothesized that in human immunodeficiency virus-associated sensory neuropathy (HIV-SN), damaged mtDNA accumulates in distal nerve segments, and that a spatial pattern of mitochondrial dysfunction contributes to the distal degeneration of sensory nerve fibers. METHODS: We measured levels of common deletion mutations in mtDNA and expression levels of mitochondrial respiratory chain complexes of matched proximal and distal nerve specimens from patients with and without HIV-SN. In mitochondria isolated from peripheral nerves of simian immunodeficiency virus (SIV)-infected macaques, a model of HIV-SN, we measured mitochondrial function and generation of reactive oxygen species. RESULTS: We identified increased levels of mtDNA common deletion mutation in postmortem sural nerves of patients with HIV-SN as compared to uninfected patients or HIV patients without sensory neuropathy. Furthermore, we found that common deletion mutation in mtDNA was more prevalent in distal sural nerves compared to dorsal root ganglia. In a primate model of HIV-SN, freshly isolated mitochondria from sural nerves of macaques infected with a neurovirulent strain of SIV showed impaired mitochondrial function compared to mitochondria from proximal nerve segments. INTERPRETATION: Our findings suggest that mtDNA damage accumulates in distal mitochondria of long axons, especially in patients with HIV-SN, and that this may lead to reduced mitochondrial function in distal nerves relative to proximal segments. Although our findings are based on HIV-SN, if confirmed in other neuropathies, these observations could explain the length-dependent nature of most axonal peripheral neuropathies.
Peripheral neuropathy associated with mitochondrial disease in children.
Menezes MP, Ouvrier RA.; Dev Med Child Neurol. 2012 May;54(5):407-14.
ABSTRACT: Mitochondrial diseases in children are often associated with a peripheral neuropathy but the presence of the neuropathy is under-recognized because of the overwhelming involvement of the central nervous system (CNS). These mitochondrial neuropathies are heterogeneous in their clinical, neurophysiological, and histopathological characteristics. In this article, we provide a comprehensive review of childhood mitochondrial neuropathy. Early recognition of neuropathy may help with the identification of the mitochondrial syndrome. While it is not definite that the characteristics of the neuropathy would help in directing genetic testing without the requirement for invasive skin, muscle or liver biopsies, there appears to be some evidence for this hypothesis in Leigh syndrome, in which nuclear SURF1 mutations cause a demyelinating neuropathy and mitochondrial DNA MTATP6 mutations cause an axonal neuropathy. POLG1 mutations, especially when associated with late-onset phenotypes, appear to cause a predominantly sensory neuropathy with prominent ataxia. The identification of the peripheral neuropathy also helps to target genetic testing in the mitochondrial optic neuropathies. Although often subclinical, the peripheral neuropathy may occasionally be symptomatic and cause significant disability. Where it is symptomatic, recognition of the neuropathy will help the early institution of rehabilitative therapy. We therefore suggest that nerve conduction studies should be a part of the early evaluation of children with suspected mitochondrial disease.
Peripheral Neuropathy in Older Patients
The prevalence, predictors, and consequences of peripheral sensory neuropathy in older patients.
Mold JW, Vesely SK, Keyl BA, Schenk JB, Roberts M., J Am Board Fam Pract. 2004 Sep-Oct;17(5):309-18.
ABSTRACT: BACKGROUND: The prevalence, predictors, and consequences of peripheral neuropathy in the elderly have not been well defined. METHODS: Seven hundred ninety-five noninstitutionalized patients 65 years of age and older, recruited from the practices of family physicians, completed questionnaires and underwent peripheral neurologic examinations and tests of gait and balance. Variables included sociodemographic information, medical conditions, symptoms (numbness, pain, trouble with balance or walking, and restless legs), quality of life measures, ankle reflexes, position sense, vibratory sense, fine touch sensation, Tinnetti balance examination, and a 50-foot timed walk. RESULTS: The prevalence of at least one bilateral sensory deficit rose from 26% for 65- to 74-year-olds to 54% for those 85 and older. The most common deficit was loss of ankle reflex followed by loss of fine touch. Only 40% of those with bilateral deficits reported having a disease known to cause peripheral neuropathy. Predictors of bilateral deficits included increasing age, income less than 15,000 dollars, a history of military service, increasing body mass index, self-reported history of diabetes mellitus, Vitamin B12 deficiency or rheumatoid arthritis, and absence of a history of hypertension. Deficits were associated with numbness, pain, restless legs, trouble walking, trouble with balance, and reduced quality of life. CONCLUSIONS: Peripheral sensory deficits are common in the elderly. In most cases, a medical cause is not obvious. Their consequences may not be as benign as often supposed.
Disorders of cobalamin (Vitamin B12) metabolism: Emerging concepts in pathophysiology, diagnosis and treatment.
Lawrence R. Solomon, Blood Rev. 2007 May;21(3):113-30. Epub 2006 Jul 11.
Although cobalamin (vitamin B12) was isolated almost 60 years ago, its biochemical, physiologic and neurologic effects remain incompletely defined. New observations suggest renal regulation of cobalamin metabolism; actions of cobalamin on nucleic acid and protein function; and a role for cobalamin in cytokine and growth factor regulation. Clinically, no gold standard has emerged for the diagnosis of cobalamin deficiency. Moreover, cobalamin resistance may occur in diabetes, renal insufficiency and advanced age, leading to functional cobalamin deficiency despite adequate cobalamin nutriture. Finally, high-dose cobalamin therapy may have salutary pharmacologic effects on neurologic function in a variety of disorders. Many studies lacked appropriate control groups. However, at this time, therapeutic trials with pharmacologic doses of cobalamin are suggested when findings consistent with cobalamin deficiency are present regardless of the results of diagnostic tests. While oral cobalamin immediate-release is adequate for many patients, its effectiveness in reversing neurologic abnormalities has yet to be established.
An update on cobalamin deficiency in adults.
Dali-Youcef N, Andrès E., QJM. 2009 Jan;102(1):17-28. doi: 10.1093/qjmed/hcn138. Epub 2008 Nov 5.
Cobalamin (vitamin B12) deficiency is particularly common in the elderly (>65 years of age), but is often unrecognized because of its subtle clinical manifestations; although they can be potentially serious, particularly from a neuropsychiatric and hematological perspective. In the general population, the main causes of cobalamin deficiency are pernicious anemia and food-cobalamin malabsorption. Food-cobalamin malabsorption syndrome, which has only recently been identified, is a disorder characterized by the inability to release cobalamin from food or its binding proteins. This syndrome is usually caused by atrophic gastritis, related or unrelated to Helicobacter pylori infection, and long-term ingestion of antacids and biguanides. Besides these syndromes, mutations in genes encoding endocytic receptors involved in the ileal absorption and cellular uptake of cobalamin have been recently uncovered and explain, at least in part, the hereditary component of megaloblastic anemia. Management of cobalamin deficiency with cobalamin injections is currently well codified, but new routes of cobalamin administration (oral and nasal) are being studied, especially oral cobalamin therapy for food-cobalamin malabsorption.