AN IN-VITRO EPR STUDY OF THE FREE-RADICAL SCAVENGING ACTIONS OF THE LAZAROID ANTIOXIDANTS U-74500A AND U-78517F

Oxygen-based free radicals have been shown to play a major role in the acute destruction of neurons following cerebral ischemia and may be i nvolved in the chronic neurodegeneration seen in Parkinson's disease, Alzheimer's disease, and other conditions characterized by the progres sive death of neurons in the central nervous system. Drugs belonging t o a group of antioxidant compounds, collectively known as the lazaroid s, have strong neuroprotective effects in experimental models of acute ischemia. However, the specific mechanisms by which these drugs reduc e the harmful actions of free radicals have not been established. Usin g electron paramagnetic resonance (EPR) spectroscopy with spin trappin g, we investigated the interaction of U-74500A, a first-generation laz aroid, and U-78517F, a second-generation lazaroid, with two species of oxygen-based free radicals in aqueous solution and with the stable ni trogen-based free radical diphenylpicrylhydrazyl in dimethyl sulfoxide . Superoxide radicals were generated by the action of xanthine oxidase on hypoxanthine. Hydroxyl radicals were generated by the Fenton react ion involving aqueous ferrous iron and hydrogen peroxide. Both lazaroi ds reduce the EPR signal of all three radicals, but the drugs differ i n potency and relative radical selectivity. These observations are con sistent with the lazaroids being scavengers of oxygen-based and nitrog en-based free radicals and suggest that the neuroprotective actions of the lazaroids in cerebral ischemia may involve direct interactions of the lazaroids with several different species of free radicals.