The Importance of MPP+ Localization for the Manifestation of MPTP-Induced Neurotoxicity
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin which is very effective in inducing a lesion of the dopaminergic nigrostriatal pathway in several species, including humans, monkeys and mice (Davis et al., 1979; Burns et al., 1983; Langston et al., 1984.; Heikkila et al., 1984a). MPTP provides a means with which to produce dopaminergic deficits in experimental animals which closely mimic those of human Parkinson’s disease. However, the degree of dopaminergic neurotoxicity induced by a given dose of MPTP can vary greatly in these species. For example, rats and mice exhibit marked differences in sensitivity to MPTP, with the rat being relatively unaffected by a dose of MPTP which would produce an 80–90% loss of dopamine in the neostriata of mice. Additionally, there is a considerable difference in sensitivity to MPTP among several strains of mice (Sonsalla and Heikkila, 1986; Sundstrom et al, 1987), and even within a particular strain, older mice are affected to a greater extent than are younger mice by a given dose of MPTP (Ricaurte et al., 1987). In some cases, as with the strains of mice, the differential sensitivity to MPTP-induced neurotoxicity may be explained by the pharmacokinetics of MPTP. More specifically, the amount of the 1-methyl-4-phenylpyridinium species (MPP+), the neurotoxic oxidation product of MPTP, which is found in the neostriata of a particular strain of mice correlates positively with the degree of dopaminergic neurotoxicity induced by MPTP in that strain, relative to the other strains. These data suggest that the brain level, or perhaps more importantly the neostriatal level, of MPP+ is a determinant of MPTP-induced dopaminergic neurotoxicity. Moreover, MAO-B inhibitors have been shown to block the formation of MPP+ in the brain of MPTP-treated animals and also to protect against MPTP-induced neurotoxicity (Heikkila et al., 1984b). In other studies, dopamine uptake inhibitors have been shown to protect against MPTP-induced neurotoxicity, presumably by preventing MPP+ accumulation by dopaminergic nerve terminals (Javitch et al., 1985; Mayer et al., 1986).
KeywordsDopamine Uptake MPTP Administration Dopaminergic Neurotoxicity Dopaminergic Deficit Dopaminergic Nigrostriatal Pathway
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- Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc. Natl. Acad. Sci. U.S.A., 82, 2173–2177.PubMedCrossRefGoogle Scholar
- Reinhard JF Jr, Daniels AJ, Viveros OH (1988) Potentiation by reserpine and tetrabenazine of brain catecholamine depletions by MPTP (1-methyl-4-phenyl-l,2,3,6tetrahydropyridine) in the mouse; evidence for subcellular sequestration as basis for cellular resistance to the toxicant. Neurosci.Lett., 90, 349–353.PubMedCrossRefGoogle Scholar
- Youngster SK, Heikkila RE (1988) A biological evaluation of some 2’-substituted analogs of MPTP, in: “Progress in Parkinson Research,” F. Hefti and W.J.Weiner, Eds., Plenum Press, New York.Google Scholar
- Youngster SK, Nicklas WJ, Heikkila RE (1989) Structure-activity study of the mechanism of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. II. Evaluation of the biological activity of the pyridinium metabolites formed from the monoamine oxidase-catalyzed oxidation of MPTP analogs. J. Pharmacol. ExDtl. Ther., 249, 829–835.Google Scholar