MPP⁺ produces progressive neuronal degeneration which is mediated by oxidative stress

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces Parkinsonism, is mediated by its metabolite 1-methyl-4-phenylpyridinium ion (MPP⁺). When injected into the striatum MPP⁺ is accumulated by dopaminergic nerve terminals and is then retrogradely transported to the substantia nigra compacta. The mechanism by which it mediates cell death involves both inhibition of complex I of the electron transport chain and free radical generation. In the present experiments we found that administration of the free radical spin trap N-tert-butyl-α-(2-sulfophenyl) nitrone (S-PBN) significantly attenuated substantia nigra cell loss produced by MPP⁺ administration into rat striatum. We also found that coadministration of coenzyme Q₁₀ with nicotinamide, which attenuates energy depletion, significantly blocked MPP⁺-induced substantia nigra damage. Last, we found that a single administration of MPP⁺ into rat striatum can produce progressive cell loss in the substantia nigra and that administration of S-PBN starting 7 days after administration of MPP⁺ can block the ensuing neuronal damage. These observations suggest that a one-time exposure to a neurotoxic agent may result in progressive neuronal degeneration mediated by oxidative stress.