Monoamine content in the rat brain structures with MPTP-induced depressive syndrome
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Norepinephrine (NE) depletion caused by damage to locus ceruleus neurons was shown to worsen experimental Parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys and in rodents. However, it is not clear whether the lesion to the NE system enhances neurotoxicity in the nigrostriatal dopaminergic (DA) pathway and/or impairs the recovery of DA neurons once the neurotoxic insult is generated. In this study, we provide evidence that the lesion of NE terminals, induced by the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg), must occur before MPTP (30 mg/kg) administration in order to enhance MPTP toxicity. As a second step, we evaluated the acute effects of MPTP on the nigrostriatal DA pathway in NE-lesioned animals compared with intact animals. We observed a more marked acute DA depletion, persisting at 12 h, in DSP-4 + MPTP-treated mice compared with MPTP-injected controls. These findings, combined with the lack of an MPTP enhancement when NE depletion was induced 12 h after MPTP administration, suggest that in NE-depleted animals, a more pronounced acute neuronal sensitivity to MPTP occurs. In line with the hypothesis of an acute protective effect by NE axons, we evaluated whether the enhancement of MPTP toxicity in NE-lesioned animals is achieved through alterations to the kinetics of MPTP and its metabolite. Our findings indicate that despite the pivotal role of NE terminals in taking up and storing 1-methyl-4-phenylpyridinium (MPP+), MPTP enhancement does not depend on modifications in the striatal kinetics of MPTP/MPP+ measured at seven different time intervals after MPTP administration.
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There are marked species differences in susceptibility to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice are sensitive, whereas rats are relatively insensitive to MPTP. In these two species, the effects of peripherally administered MPTP or intrastriatally infused 1-methyl-4-phenylpyridinium (MPP+) were examined to identify potential underlying mechanisms responsible for their difference in susceptibility to MPTP. In vivo intrastriatal microdialysis and an MPP+ 2-day test/challenge paradigm were used to monitor dopamine efflux as an indicator of the neurotoxic effects of MPTP or MPP+. By using this method, the EC50 for neurotoxicity by an intrastriatal infusion of MPP+ in mice was 0.4 mM, whereas it was 10-fold higher in rats (4.3 mM). In addition, by using the traditional postmortem examination, neostriatal dopamine was depleted markedly in mice (> or = 80%), but only depleted marginally in rats in which MPP+ was infused into the neostriatum. These data indicate that rats are relatively insensitive to MPTP as compared to mice, because they are less sensitive to MPP+ whether it is formed in vivo from MPTP administered systemically or administered directly into neostriata. Thus, there appears to be a fundamental difference in the susceptibility of the nigrostriatal systems in these two species to the neurotoxic consequences of MPP+ exposure.
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The discovery of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a parkinsonism-producing neurotoxin (Davis et al., 1979; Langston et al., 1983) has greatly contributed to the pathogenesis of Parkinson's disease. Efforts have been made to find MPTP-like neurotoxins in the brain of parkinsonian patients. MPTP is a precursor neurotoxin, and the oxidized form, by monoamine oxidase type B, N-methyl-4-phenylpyridinium ion (MPP+), is the active neurotoxin (Chiba et al., 1984). It is assumed, therefore, that if any hypothetical MPTP-like neurotoxins exist in the parkinsonian brain they might be oxidized by monoamine oxidase to active neurotoxins.
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Mechanism of Action
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Although much progress have been made in recent years, the etiology of idiopathic Parkinson's disease remains obscure. The chance discovery that injection of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a syndrome very similar to parkinsonism introduced the "environmental toxin" hypothesis but no toxin was ever found in any quantity in patients' brains. We have unexpectedly now found, however, that, in mice, very low doses of MPTP induce as much dopaminergic neuronal death as far higher doses. Cellular detoxification mechanisms would appear to be incapacitated at such low doses. This could infer that the barely discernible presence of an unidentified neurotoxin may be responsible for the onset of Parkinson's disease.
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