THIOCTIC (LIPOIC) ACID - A THERAPEUTIC METAL-CHELATING ANTIOXIDANT

Thioctic (alpha-lipoic) acid (TA) is a drug used for the treatment of diabetic polyneuropathy in Germany. It has been proposed that TA acts as an antioxidant and interferes with the pathogenesis of diabetic pol yneuropathy. We suggest that one component of its antioxidant activity requiring study is the direct transition metal-chelating activity of the drug. We found that TA had a profound dose-dependent inhibitory ef fect upon Cu2+-catalysed ascorbic acid oxidation (monitored by O-2 upt ake and spectrophotometrically at 265 nm) and also increased the parti tion of CU2+ into n-octanol from an aqueous solution suggesting that T A forms a lipophilic complex with CU2+. TA also inhibited Cu2+-catalys ed liposomal peroxidation. Furthermore, TA inhibited intracellular H2O 2 production in erythrocytes challenged with ascorbate, a process thou ght to be mediated by loosely chelated CU2+ within the erythrocyte. Th ese data, taken together, suggest that prior intracellular reduction o f TA to dihydrolipoic acid is not an obligatory mechanism for an antio xidant effect of the drug, which may also operate via Cu2+-chelation. The R-enantiomer and racemic mixture of the drug (alpha-TA) generally seemed more effective than the S-enantiomer in these assays of metal c helation.