MPP(+) PRODUCES PROGRESSIVE NEURONAL DEGENERATION WHICH IS MEDIATED BY OXIDATIVE STRESS

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, whi ch produces Parkinsonism, is mediated by its metabolite 1-methyl-4-phe nylpyridinium ion (MPP(+)). When injected into the striatum MPP(+) is accumulated by dopaminergic nerve terminals and is then retrogradely t ransported to the substantia nigra compacta. The mechanism by which it mediates cell death involves both inhibition of complex I of the elec tron transport chain and free radical generation. In the present exper iments we found that administration of the free radical spin trap N-te rt-butyl-alpha-(2-sulfophenyl) nitrone (S-PBN) significantly attenuate d substantia nigra cell loss produced by MPP(+) administration into ra t striatum. We also found that coadministration of coenzyme Q(10) with nicotinamide, which attenuates energy depletion, significantly blocke d MPP(+)-induced substantia nigra damage. Last, we found that a single administration of MPP(+) into rat striatum can produce progressive ce ll loss in the substantia nigra and that administration of S-PBN start ing 7 days after administration of MPP(+) can block the ensuing neuron al damage. These observations suggest that a one-time exposure to a ne urotoxic agent may result in progressive neuronal degeneration mediate d by oxidative stress. (C) 1997 Academic Press.