A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Abstract

A syndrome similar to idiopathic parkinsonism developed after intravenous self-administration of an illicit drug preparation in which N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) might have been responsible for the toxicity. In the present study we show that intravenous administration of NMPTP to the rhesus monkey produces a disorder like parkinsonism (akinesia, rigidity, postural tremor, flexed posture, eyelid closure, drooling) that is reversed by the administration of L-dopa. NMPTP treatment decreases the release of dopamine and dopamine accumulates in swollen, distorted axons in the nigrostriatal pathway just above the substantia nigra, followed by severe nerve cell loss in the pars compacta of the substantia nigra and a marked reduction in the dopamine content of the striatum. The pathological and biochemical changes produced by NMPTP are similar to the well-established changes in patients with parkinsonism. Thus, the NMPTP-treated monkey provides a model that can be used to examine mechanisms and explore therapies of parkinsonism.The most prominent pathological change in idiopathic parkinsonism is degeneration of the nigrostriatal dopaminergic pathway with nerve cell loss in the substantia nigra (1). A neurochemical consequence of this loss of dopaminergic neurons is a marked decrease in the concentrations of dopamine and its major metabolite homovanillic acid (HVA) in the caudate nucleus and putamen (2). The effectiveness of L-dopa and directacting dopamine agonists in reversing akinesia, rigidity, resting tremor, and postural abnormalities in patients with idiopathic parkinsonism (3, 4) reflects the pathophysiology of these clinical signs.In 1979 a single case of parkinsonism occurring after intravenous self-administration of an illicit narcotic analgesic was described (5). Recently, a series of similar cases has been reported (6). We had the opportunity to examine two patients included in the later study. In both instances there was evidence that the method of Ziering et al. (7) had been used to synthesize the reverse ester of meperidine, 4-propionoxy-4-phenyl-N-methylpiperidine. The injected mixture also contained the side product N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP). After intravenous administration of multiple doses of the drug mixture over several days, the patients gradually developed persistent symptoms of parkinsonism, with a syndrome characterized by severe akinesia, rigidity, a flexed posture, and a resting tremor associated with low concentrations of HVA in the lumbar cerebrospinal fluid (5-6.7 ng/ml). The clinical signs were reversed by the administration of L-dopa or bromocriptine. A marked loss of pigmented cells in the substantia nigra with minimal changes in the locus ceruleus was found in the one patient who died of other causes 18 months after the onset of symptoms (5).In the present study we show that repeated intravenous administration of NMPTP to the rhesus monkey over a period of 5-8 days produces a chronic disorder with neurological, biochemical, pa...

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“…The dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP] is known to induce parkinsonism in hu-mans, primates, and mice ( [27,90,132,133]). MPTP is converted by astrocytes to the metabolite 1 methyl-4-phenylpyridinium [MPP + ], a substrate of the DA transporter ( [40,41]).…”

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

“…The cardinal clinical symptoms are bradykinesia, tremor, rigidity, and postural instability with the pathological characteristic of evolutional nigrostriatal dopaminergic neurodegeneration [2,3] . 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that induces parkinsonism in both humans [4] and non-human primates [5] with the cognitive, biochemical, histological and classical behavioral changes that occur in PD [6] . Therefore, Increasing evidence has suggested that single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging can be used to sensitively and objectively evaluate the integrity of the nigrostriatal dopaminergic system and may be useful tools for providing diagnostic information on PD [7][8][9][10] .…”

The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

“…Administration of MPTP to man or non-human primates (Davis et al 1979;Langston et al 1983;Burns et al 1983) including common marmosets (Jenner et al 1984) induces a selective destruction of dopaminergic nigrostriatal neurons associated with a substantial decrease in dopamine content of the caudate nucleus and putamen. MPTP is converted by monoamine oxidase type B (MAO-B) into the dihydropyridinium species (MPDP ÷) which is converted non-enzymatically into the neurotoxic l-methyl-4-phenylpyridinium ion (MPP ÷; Castagnoli et al 1985).…”