Alpha-lipoic Acid and diabetic neuropathy

Diabetes, 1999

The peripheral nerve of experimental diabetic neuropathy (EDN) is reported to be ischemic and hypoxic, with an increased dependence on anaerobic metabolism, requiring increased energy substrate stores. When glucose stores become reduced, fiber degeneration h a s been reported. We evaluated glucose uptake, nerve energy metabolism, the polyol pathway, and protein kinase C (PKC) activity in EDN induced by streptozotocin. Control and diabetic rats received lipoic acid (0, 10, 25, 50, 100 mg/kg). Duration of diabetes was 1 month, and ␣-lipoic acid was administered intraperitoneally 5 times per week for the final week of the experiment. Nerve glucose uptake was reduced to 60, 37, and 30% of control values in the sciatic nerve, L5 dorsal root ganglion, and superior cervical ganglion (SCG), respectively, in rats with EDN. ␣-Lipoic acid supplementation had no effect on glucose uptake in normal nerves at any dose, but reversed the deficit in EDN, with a threshold between 10 and 25 mg/kg. Endoneurial glucose, fructose, sorbitol, and m y o-i n o s i t o l w e r e measured in sciatic nerve. ␣-Lipoic acid had no significant effect on either energy metabolism or polyol pathway of normal nerves. In EDN, endoneurial glucose, fructose, and sorbitol were significantly increased, while m y o-inositol was significantly reduced. ␣-Lipoic acid had a biphasic effect: it dose-dependently increased f r u ctose, glucose, and sorbitol, peaking at 25 mg/kg, and then fell beyond that dose, and it dose-dependently increased m y o-inositol. Sciatic nerve cytosolic PKC was increased in EDN. AT P, creatine phosphate, and lactate were measured in sciatic nerve and SCG. ␣-Lipoic acid prevented the reduction in SCG creatine phosphate. We conclude that glucose uptake is reduced in EDN and that this deficit is dose-dependently reversed by ␣-lipoic acid, a change associated with an improvement in peripheral nerve function. D i a b e t e s 48:2045-2051, 1999 E xperimental diabetic neuropathy (EDN), induced RESEARCH DESIGN AND METHODS Experimental animals. We used a total of 263 male Sprague-Dawley rats, beginning weight 250 ± 5 g. They were fed Purina Rodent Laboratory Chow (no. 5001; Richmond, IN) with a liberal supply of water and were housed in plastic containers whose floors were covered with wood shavings. The study was done in multiple stages. Stage 1 was a study on glucose uptake. A total of 102 rats were divided into the following groups, with at least seven rats in each group: Group 1: Controls without ␣-lipoic acid (C0) Group 2: Controls + ␣-lipoic acid 10 mg/kg (C10) Group 3: Controls + ␣-lipoic acid 25 mg/kg (C25)

Diabetes Care, 1995

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-d...

Eur J Clin Invest, 2001

Background Increased oxidative stress is considered to be a causal factor in the development of diabetic complications, among which peripheral neuropathy. The pathophysiology of nerve dysfunction in diabetes has been explained both by reduced endoneurial microcirculation and alterations in endoneurial metabolism. It is unclear whether antioxidants primarily improve nerve blood flow or normalise systemic or endoneurial oxidative metabolism. Therefore, we evaluated the effects of the antioxidants glutathione and a-lipoic acid on both nerve microcirculation and the antioxidative capacity and lipid peroxidation in experimentally diabetic rats.

Drug Metabolism Reviews, 1997

International journal of Pharmacy and Pharmaceutical Sciences, 2014

Objective: Diabetic peripheral neuropathy is the most common long term complications associated with reduced nerve conduction and blood flow. The present study was designed to investigate the effect of oral supplementation of α-lipoic acid (600 mg/day) on peripheral, sensory and motor nerve conduction and glycaemic control in type 2 diabetes mellitus with peripheral neuropathy. Methods: A total of 20 patients were enrolled in this study, then randomly allocated to two groups control (n=10) and intervention group (n=10). Patients in control group received only oral hypoglycaemic treatment and in intervention group received α-lipoic acid (600 mg/day) oral supplementation along with their oral hypoglycaemic treatment for a period of 3 months. Nerve conduction and glycaemic control were measured at the base line and at the end of 3 months by using specific methods. Results: In intervention group α-lipoic acid supplementation significantly improves 6 of 15 electrophysiological parameters of nerve conduction. Distal latency of peroneal (mean ± SD 5.13 ± 0.52 vs 4.92±0.55; p<0.02), median (mean ± SD 3.66 ± 0.76 vs 3.53±0.63; p<0.03) & ulnar motor nerves (mean ± SD 2.91 ± 0.32 vs 2.82±0.36; p<0.01), and Nerve Conduction Velocity of peroneal (mean ± SD 42.0 ± 3.07 vs 43.4±2.13; p<0.03), median (mean ± SD 51.4 ± 3.31 vs 52.2±3.59; p<0.01) & ulnar motor nerves (mean ± SD 51.0 ± 5.84 vs 52.1±5.46; p<0.03) shows significant improvement. Conclusion: Oral supplementation of α-lipoic acid was found to be effective in improving motor nerve conduction of upper and lower extremities in patients with diabetic peripheral neuropathy.

Diabetes Research and Clinical Practice, 1999

Reactive oxygen species (ROS) are elevated by metabolic changes in diabetes, including autoxidation and increased advanced glycation. Endogenous protection by the glutathione redox cycle is also compromised by the competing NADPH requirement of elevated polyol pathway flux. Antioxidant treatment strategies prevent or reverse nerve conduction velocity (NCV) deficits in diabetic rats. These include lipophilic scavengers such as butylated hydroxytoluene, probucol and vitamin E, more hydrophilic agents like a-lipoic acid and acetyl cysteine, and transition metal chelators that inhibit autoxidation. In the long-term, elevated ROS cause cumulative damage to neurons and Schwann cells, however, they also have a deleterious effect on nerve blood flow in the short term. This causes endoneurial hypoxia, which is responsible for early NCV deficits. Antioxidant treatment corrects the blood flow deficit and promotes normal endoneurial oxygenation. ROS cause antioxidant-preventable vascular endothelium abnormalities, neutralizing nitric oxide mediated vasodilation and increasing reactivity to vasoconstrictors. Unsaturated fatty acids are a major target for ROS and essential fatty acid metabolism is impaired by diabetes. g-Linolenic acid stimulates vasodilator prostanoid production, and there are marked synergistic interactions between g-linolenic acid and antioxidants. This has encouraged the development of novel drugs such as ascorbyl-g-linolenic acid and g-linolenic acid-lipoic acid with enhanced therapeutic potential.

Free Radical Biology and Medicine, 2001

Oxidative stress contributes to the vascular and neurological complications of diabetes mellitus. The aim was to evaluate the effects of treatment with the radical scavenger and transition metal chelator, ␣-lipoic acid, on endothelium-dependent relaxation of the mesenteric vasculature and on superior cervical ganglion blood flow in 8 week streptozotocin-induced diabetic rats. ␣-Lipoic acid effects on small nerve fiber-mediated nociception were also monitored. For the in vitro phenylephrine-precontracted mesenteric vascular bed, diabetes caused a 31% deficit in maximum endothelium-dependent relaxation to acetylcholine, and a 4-fold reduction in sensitivity. ␣-Lipoic acid gave 85% protection against these defects. Acetylcholine responses are mediated by nitric oxide and endothelium-derived hyperpolarizing factor: isolation of the latter by nitric oxide synthase blockade revealed a 74% diabetic deficit that was halved by ␣-lipoic acid. Superior cervical ganglion blood flow, 52% reduced by diabetes, was dose-dependently restored by ␣-lipoic acid (ED 50 , 44 mg/kg/d). Diabetic rats exhibited mechanical and thermal hyperalgesia, which were abolished by ␣-lipoic acid treatment. Thus, diabetes impairs nitric oxide and endothelium-derived hyperpolarizing factor-mediated vasodilation. This contributes to reduced neural perfusion, and may be responsible for altered nociceptive function. The effect of ␣-lipoic acid strongly implicates oxidative stress in these events and suggests a potential therapeutic approach.

Medical Journal of Indonesia, 2011

Latar belakang: Di Jerman, asam lipoid terdaftar dengan indikasi "polineuropati perifer diabetik". Laporan kasus ini bermaksud mempertunjukkan aktivitas terapetik yang melebihi indikasi ini. Di Indonesia, substansi ini tidak terdaftar untuk terapi.

Frontiers in Pharmacology, 2011

Diabetes mellitus is a multi-faceted metabolic disorder where there is increased oxidative stress that contributes to the pathogenesis of this debilitating disease. This has prompted several investigations into the use of antioxidants as a complementary therapeutic approach. Alpha lipoic acid, a naturally occurring dithiol compound which plays an essential role in mitochondrial bioenergetic reactions, has gained considerable attention as an antioxidant for use in managing diabetic complications. Lipoic acid quenches reactive oxygen species, chelates metal ions, and reduces the oxidized forms of other antioxidants such as vitamin C, vitamin E, and glutathione. It also boosts antioxidant defense system through Nrf-2-mediated antioxidant gene expression and by modulation of peroxisome proliferator activated receptors-regulated genes. ALA inhibits nuclear factor kappa B and activates AMPK in skeletal muscles, which in turn have a plethora of metabolic consequences. These diverse actions suggest that lipoic acid acts by multiple mechanisms, many of which have only been uncovered recently. In this review we briefly summarize the known biochemical properties of lipoic acid and then discussed the oxidative mechanisms implicated in diabetic complications and the mechanisms by which lipoic acid may ameliorate these reactions. The findings of some of the clinical trials in which lipoic acid administration has been tested in diabetic patients during the last 10 years are summarized. It appears that the clearest benefit of lipoic acid supplementation is in patients with diabetic neuropathy.

The Cochrane library, 2018

Alpha-lipoic acid for diabetic peripheral neuropathy.