EFFECTS OF ALPHA-LIPOIC ACID ON NEUROVASCULAR FUNCTION IN DIABETIC RATS - INTERACTION WITH ESSENTIAL FATTY-ACIDS

Elevated oxidative stress and impaired n-6 essential fatty acid metabo lism contribute to defective nerve conduction velocity (NCV) and perfu sion in diabetic rats, which may be corrected by free radical scavenge r and gamma-linolenic acid (GLA) treatments. alpha-lipoic acid (LPA) h as antioxidant actions and both LPA racemate (racLPA) and GLA treatmen ts produced benefits in clinical neuropathy trials. The aims were to s tudy LPA action on neurovascular function in diabetic rats and to inve stigate potential interac tions for co-treatment with GLA and other es sential fatty acids. After 6 weeks of diabetes, 2 weeks of racLPA trea tment corrected 20 % sciatic motor and 14% saphenous sensory NCV defic its. The ED50 for motor NCV restoration was approximately 35 mg.kg(-1) .day(-1). racLPA also corrected a 49 % diabetic deficit in sciatic end oneurial blood flow. R and S-LPA enantiomers were equipotent in correc ting 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 ef fects on their own, showed evidence of marked synergistic action in jo int 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 (ED50 9.3 mg.kg(-1).day(-1), cont aining 3.5mg LPA). NCV effects also showed marked synergism when racLP A: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 si milar activity to LPA alone. Thus, LPA-GLA interactions yield drug com binations and compounds with an order of magnitude increase in efficac y against experimental diabetic neuropathy and are worthy of considera tion for clinical trials.