The Importance of MPP⁺ Localization for the Manifestation of MPTP-Induced Neurotoxicity

Abstract

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).