THE PHARMACOLOGY OF THE ANTIOXIDANT LIPOIC ACID

1. Lipoic acid is an example of an existing drug whose therapeutic eff ect has been related to its antioxidant activity. 2. Antioxidant activ ity is a relative concept: it depends on the kind of oxidative stress and the kind of oxidizable substrate (e.g., DNA, lipid, protein), 3. I n vitro, the final antioxidant activity of lipoic acid is determined b y its concentration and by its antioxidant properties. Four antioxidan t properties of lipoic acid have been studied: its metal chelating cap acity, its ability to scavenge reactive oxygen species (ROS), its abil ity to regenerate endogenous antioxidants and its ability to repair ox idative damage. 4. Dihydrolipoic acid (DHLA), formed by reduction of l ipoic acid, has more antioxidant proper ties than does lipoic acid. Bo th DHLA and lipoic acid have metal-chelating capacity and scavenge ROS , whereas only DHLA is able to regenerate endogenous antioxidants and to repair oxidative damage. 5. As a metal chelator, lipoic acid was sh own to provide antioxidant activity by chelating Fe2+ and Cu2+; DHLA c an do so by chelating Cd2+. 6. As scavengers of ROS, lipoic acid and D HLA display antioxidant activity in most experiments, whereas, in part icular cases, pro-oxidant activity has been observed. However, lipoic acid can act as an antioxidant against the pro-oxidant activity produc ed by DHLA. 7. DHLA has the capacity to regenerate the endogenous anti oxidants vitamin E, vitamin C and glutathione. 8. DHLA can provide pep tide methionine sulfoxide reductase with reducing equivalents. This en hances the repair of oxidatively damaged proteins such as alpha-1 anti protease. 9. Through the lipoamide dehydrogenase-dependent reduction o f lipoic acid, the cell can draw on its NADH pool for antioxidant acti vity additionally to its NADPH poor, which is usually consumed during oxidative stress. 10. Within drug-related antioxidant pharmacology, li poic acid is a model compound that enhances understanding of the mode of action of antioxidants in drug therapy. (C) 1997 Elsevier Science I nc.