Aging and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of dopaminergic neurons in the substantia nigra

This study assessed the influence of aging on substantia nigra degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive neuronal degeneration was found in the substantia nigra of older (8–12 months of age) but not younger (6–8 weeks of age) mice given MPTP. Older mice did not have higher brain concentrations of either MPTP or 1-methyl-4-phenylpyridinium (MPP⁺), the putative toxic metabolite of MPTP, to account for the greater toxicity. In fact, older mice metabolized MPTP more rapidly than younger mice, probably because of the increase in monoamine oxidase activity that occurs with aging. Striatal synaptosomes from older mice did not accumulate more ³H]MPP⁺ than synaptosomes from younger mice. Thus, it is concluded that the greater neurodegenerative effect of MPTP in older animals is not due to greater levels or uptake of MPP⁺, but rather is related to a true increase in sensitivity of older dopaminergic cells to MPTP. For comparative purposes, the toxic effect of another dopaminergic neurotoxin, methamphetamine, was tested. Older animals were not more sensitive than young mature animals to the toxic effect of methamphetamine. This finding indicates that the increased sensitivity of older dopaminergic neurons to MPTP is selective. The link established here between aging and the neurodegenerative effect of MPTP, a toxin which produces parkinsonism in humans, provides a mechanism by which an age-related neurodegenerative disorder such as Parkinson's disease could be caused by an MPTP-like toxin in the environment.