Effects of α-lipoic acid on neurovascular function in diabetic rats: interaction with essential fatty acids

Abstract

Oxidative stress contributes to the vascular and neuropathic complications of experimental diabetes mellitus. This is evidenced by measures of tissue oxidant damage such as nerve lipid peroxidation and changes in antioxidant protection systems, for example decreased nerve reduced glutathione (GSH) and superoxide dismutase content [1,2]. Functional effects of antioxidant treatment include protection of vascular endothelium function [3±5], and improved nerve blood flow, conduction velocity (NCV) and regenerative capacity [2, 6±10]. a-Lipoic acid (LPA) is a naturally occurring free radical scavenger and transition metal chelator. LPA is also a cofactor for mitochondrial pyruvate dehydrogenase and has been termed a ªmetabolic antioxidantº [11]. Recent studies from Low's group [2,12] showed that treatment with LPA racemate (racLPA) prevented the development of digital sensory NCV deficits, impaired sciatic nerve blood flow, diminished nerve GSH, and deficient glucose uptake by neural tissues in diabetic rats. Short- Diabetologia (1998) Summary Elevated oxidative stress and impaired n-6 essential fatty acid metabolism contribute to defective nerve conduction velocity (NCV) and perfusion in diabetic rats, which may be corrected by free radical scavenger and g-linolenic acid (GLA) treatments. a-Lipoic acid (LPA) has antioxidant actions and both LPA racemate (racLPA) and GLA treatments produced benefits in clinical neuropathy trials. The aims were to study LPA action on neurovascular function in diabetic rats and to investigate potential interactions for co-treatment with GLA and other essential fatty acids. After 6 weeks of diabetes, 2 weeks of racLPA treatment corrected 20 % sciatic motor and 14 % saphenous sensory NCV deficits. The ED 50 for motor NCV restoration was approximately 38 mg kg ±1 day ±1. racLPA also corrected a 49 % diabetic deficit in sciatic endoneurial blood flow. R and S-LPA enantiomers were equipotent in correcting NCV and blood flow deficits. Treatment of diabetic rats with low doses (20 mg kg ±1 day ±1 ) of racLPA and GLA, while having modest effects on their own, showed evidence of marked synergistic action in joint treatment, completely correcting motor NCV and blood flow deficits. This was also noted for the novel compound, SOC0150, which contains equimolar proportions of LPA and GLA (ED 50 9.3 mg kg ±1 day ±1 , containing 3.5 mg LPA). NCV effects also showed marked synergism when racLPA:GLA ratios were varied over a 1:3±3:1 range. In contrast, a compound containing LPA and the n-3 component, docosahexaenoic acid, showed similar activity to LPA alone. Thus, LPA-GLA interactions yield drug combinations and compounds with an order of magnitude increase in efficacy against experimental diabetic neuropathy and are worthy of consideration for clinical trials. [Diabetologia (1998) 41: 390±399]

SOD2 protects neurons from injury in cell culture and animal models of diabetic neuropathy

“…This link supports the findings of other studies in experimental and clinical diabetes (Cameron et al, 1993;Low et al, 1997;Cameron et al, 1998;Hounsom et al, 2001). The current study explores the hypothesis that accelerating the accumulation of ROS in the peripheral nervous system will in turn accelerate the development of DN.…”

“…The idea that oxidative stress contributes to diabetic complications is widely acknowledged (Cameron et al, 1998;Vincent et al, 2004c;Low et al, 1997;Cameron et al, 1993;Hounsom et al, 2001;Brownlee, 2001). Our work focuses on understanding how hyperglycemia-induced oxidative stress contributes to diabetic neuropathy (DN).…”

Evaluation of a sorbitol dehydrogenase inhibitor on diabetic peripheral nerve metabolism: a prevention study

“…That an osmotic factor is involved is supported by decreased phosphocreatine concentrations in the peripheral nerve of rats after 10 days of feeding with 50 % galactose but not in rats which have been diabetic for 10 days (nerve galactitol accumulation in the galactose-fed rats exceeded~13-fold nerve sorbitol accumulation in the diabetic group) (I. Obrosova, unpublished observations). It is also supported by experiments with DL-a-lipoic acid which increased nerve sorbitol accumulation [44,64] and did not prevent decrease in either phosphocreatine concentrations [64] or the phosphocreatine:creatine ratio [44], in spite of the preservation of normal blood flow [16,44] and free mitochondrial NAD: NADH ratios [44], in the ªyoungº [65] streptozotocin model of diabetes. Another explanation for exacerbation of energy deficiency induced in diabetes by SDI is the possibility that the sorbitol pathway is the route providing fructose-6-phosphate for anaerobic glycolysis [66], bypassing hexokinase.…”

Effects of Intraperitoneally Administered Lipoic Acid, Vitamin E, and Linalool on the Level of Total Lipid and Fatty Acids in Guinea Pig Brain with Oxidative Stress Induced by H2O2

“…Lipoic acid has long been known for its role in oxidative metabolism, the same as lipoamide, an essential cofactor in mitochondrial α-ketoacid dehydrogenase complexes (Packer et al, 1997). Recent reports indicate that lipoate exerts its therapeutic efficacy in pathological conditions that involve free radicals (Cameron et al, 1998;Kozlov et al, 1999).…”