Novel free radical spin traps protect against malonate and MPTP neurotoxicity

Both malonate and 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) are n eurotoxins which cause energy depletion, secondary excitotoxicity, and free radical generation. Malonate is a reversible inhibitor of succinate dehydr ogenase, while MPTP is metabolized to 1-methyl-4-phenylpyridinium, an inhib itor of mitochondrial complex I. We examined the effects of pretreatment wi th the cyclic nitrone free radical spin trap MDL 101,002 on malonate and MP TP neurotoxicity. MDL 101,002 produced dose-dependent neuroprotection again st malonate-induced striatal lesions. MDL 101,002 produced significant prot ection against MPTP induced depletions of dopamine and its metabolites. MDL 101,002 also significantly attenuated MPTP-induced increases in striatal 3 -nitrotyrosine concentrations. The free radical spin trap tempol also produ ced significant protection against MPTP neurotoxicity. These findings provi de further evidence that free radical spin traps produce neuroprotective ef fects in vivo and suggest that they may be useful in the treatment of neuro degenerative diseases, (C) 1999 Academic Press.