The parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP): a technical review of its utility and safety

Abstract

Parkinson's disease (PD) is a common disabling neurodegenerative disorder the cardinal clinical features of which include tremor, rigidity and slowness of movement (Fahn and Przedborski 2000). These symptoms are attributed mainly to a profound reduction of dopamine in the striatum due to a dramatic loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Fahn and Przedborski 2000). Thus far, both the cause and the mechanisms of PD remain unknown. Over the years, investigators have used experimental models of PD produced by several compounds such as reserpine, 6-hydroxydopamine, methamphetamine, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to provide insights into the mechanisms responsible for the demise of dopaminergic neurons in PD. To this end, MPTP has emerged unquestionably as a popular tool for inducing a model of PD in a variety of animal species including monkeys, rodents, cats, and pigs (Kopin and Markey 1988). The sensitivity to MPTP and therefore its ability to induce parkinsonism closely follows the phylogenetic tree where the species most closely related to humans are the most vulnerable to this neurotoxin. Due to the significant neurotoxicity of MPTP, it is important that researchers appreciate the potential hazards of this toxin. Given this, the purpose of this review is to inform the researcher of the hazardous nature of MPTP and to provide guidance for its safe handling and use. MPTP is a by-product of the chemical synthesis of a meperidine analog with potent heroin-like effects. MPTP can induce a parkinsonian syndrome in humans almost indistinguishable from PD (Langston and Irwin 1986). Recognition of MPTP as a neurotoxin occured early in 1982, when several young drug addicts mysteriously developed a profound parkinsonian syndrome after the intravenous use of street preparations of meperidine analogs which, unknown to anyone, were contaminated with MPTP (Langston et al. 1983). In humans and non-human primates, depending on the regimen used, MPTP can produce an irreversible and severe parkinsonian syndrome that replicates almost all of the features of PD, including tremor, rigidity, slowness of movement, postural instability, and even freezing; in non-human primates, a resting tremor characteristic of PD has only been demonstrated convincingly in the African green monkey (Tetrud et al. 1986). The responses, as well as the complications, to traditional antiparkinsonian therapies are virtually identical to those seen in PD. It is believed that in PD the neurodegenerative process occurs over several years, while the most active phase of neurodegeneration is completed within a few days following MPTP administration (Langston 1987; Jackson-Lewis et al. 1995). However, recent data suggest that, following the main phase of neuronal death, MPTP-induced neurodegeneration may continue to progress 'silently' over several decades, at least in humans intoxicated with MPTP (Vingerhoets et al. 1994; Langston et al. 1999). Except for four cases (Davis et al. 1979; Langston et al. 1999), no human pathological material has been available for studies and thus, the comparison between PD and the MPTP model is largely limited to primates (Forno et al. 1993). Neuropathological data show that MPTP administration causes damage to the nigrostriatal dopaminergic pathway identical to that seen in PD (Agid et al. 1987), yet there is a resemblance that goes beyond the loss of SNpc dopaminergic neurons. Like PD, MPTP causes greater loss of dopaminergic neurons in SNpc than in ventral tegmental area (Seniuk et al. 1990; Muthane et al. 1994) and, at least in monkeys treated with low doses of MPTP but not in humans, greater degeneration of dopaminergic nerve terminals in the putamen than in the caudate nucleus (Moratalla et al. 1992; Snow et al. 2000). However, two typical neuropathologic features of PD have, until now, been lacking in the MPTP model. First, except for SNpc, pigmented nuclei such as locus coeruleus have been spared, according to most published reports. Second, the eosinophilic intraneuronal inclusions, called Lewy bodies, so characteristic of PD, thus far, have not been convincingly observed in MPTP-induced parkinsonism (Forno et al. 1993), although, in MPTP-injected monkeys, intraneuronal inclusions reminiscent of Lewy bodies have been described (Forno et al. 1986). To date, the most frequently used animals for MPTP studies are monkeys, mice and rats. The administration of MPTP through a number of different routes using different dosing regimens has led to the development of several distinct models, each characterized by some unique behavioral and/or biochemical features. The manner in which these models were developed is based on the concept of delivering MPTP in a fashion that creates the most severe and stable form of SNpc damage with the least number of undesirable consequences such as acute death, dehydration and malnutrition. Although MPTP can be given by a number of diff