RADICAL TRAPPING AND INHIBITION OF IRON-DEPENDENT CNS DAMAGE BY CYCLIC NITRONE SPIN TRAPS

Oxidative damage in the CNS is proposed to play a role in many acute a nd chronic neurodegenerative disorders. Accordingly, the nitrone spin trap alpha-phenyl-N-tert-butylnitrone (PEN), which reacts covalently w ith free radicals, has shown efficacy in a variety of animal models of CNS injury. We have synthesized a number of cyclic variants of PEN an d examined their activity as radical traps and protectants against oxi dative damage in CNS tissue. By using electron spin resonance spectros copy, the cyclic nitrones MDL 101,002 and MDL 102,832 were shown to tr ap radicals in a manner similar to that of PEN. All cyclic nitrones te sted prevented hydroxyl radical-dependent degradation of 2-deoxyribose and peroxyl radical-dependent oxidation of synaptosomes more potently than PEN. The radical scavenging properties of the cyclic nitrones co ntributed to a three- to 25-fold increase in potency relative to PEN a gainst oxidative damage and cytotoxicity in cerebellar granule cell cu ltures. Similar to the phenolic antioxidant MDL 74,722, the nitrones m inimized seizures and delayed the time to death in mice following cent ral injection of ferrous iron. Although iron-induced lipid peroxidatio n was inhibited by MDL 74,722, the nitrones had no effect on this bioc hemical end point, indicating that iron-induced mortality does not res ult solely from lipid peroxidation and suggesting additional neuroprot ective properties for the nitrones. These results indicate that cyclic nitrones are more potent radical traps and inhibitors of lipid peroxi dation in vitro than PEN, and their ability to delay significantly iro n-induced mortality in vivo suggests they may be useful in the treatme nt of acute and chronic neurodegeneration. Furthermore, the stability of the spin trap adducts of the cyclic nitrones provides a new tool fo r the study of oxidative tissue injury.