Neurotoxicity of MPTP

Ramassamy C, Clostre F, Christen Y, Costentin J. (1990). Prevention by a Ginkgo biloba extract (GBE 761) of the dopaminergic neurotoxicity of MPTP. J Pharm Pharmacol. 42(11) 785-89. 

Fig. (2). Hypothesized mechanisms of neurotoxicity of MPTP. After injection of MPTP, its native form crosses the blood brain barrier (BBB) and is oxidized by monoamine oxidase B (MAO-B) into MPP+. This metabolite is transported and concentrated into nigrostriatal dopamine and exerts a neurotoxic effect...

Nitroindazole, an inhibitor of NOS-1, and L-NAME, a less selective inhibitor of neuronal NOS, have significant antinociceptive effects in humans and animals and 7-nitroindazol reduces the signs of opioid withdrawal and cocaine action in animal models. This inhibitor also reduces cerebral blood flow. Nevertheless, 7-nitroindazole can reduce the size of cerebral infarcts in animal models. In contrast, NOS-3-deficient mice are more susceptible to ischemic cerebral damage. NOS-1 inhibition by 7-nitroindazole also reduces the neurotoxicity of MPTP and MPP+ (see Chapter 28 Pharmacologic Management of Parkinsonism Other Movement Disorders) in several animal models. 

Perinatal exposure of mice to dieldrin alters the dopaminergic neurochemistry in their offspring. Exposure to a mixture of dieldrin and MPTP during development exacerbates the neurotoxicity of MPTP, a known chemical cause of Parkinson s disease. This study serves as a model for the induction of Parkinson s disease by chemical mixtures. I26l... 

In vitro metabolic studies with rodent and human liver microsomal prepara- tions have established that MPTP undergoes both oxidative N-demethylation and C-6 (allylic) oxidation in reactions that are -nicotinamide adenine dinucleotide phosphate (NADPH) dependent and therefore likely to be cytochrome P-450 catalyzed (Weissman et al. 1985 Ottoboni et al. 1990). Although the latter transformation can lead to the toxic pyridinium metabolite MPP, the cytochrome P450-catalyzed pathway is unlikely to contribute significantly to the neurotoxicity of MPTP. As mentioned above, liver aldehyde oxidase diverts the inter-mediate dihydropyridinium metabolite away from pyridinium ion formation by catalyzing the conversion of structure 40 to the nontoxic lactim structure 41. Further-more, even if formed in the periphery, the polar pyridinium metabolite would have limited access to the central nervous system (CNS). The low... 

This drug is protective against the selective neurotoxicity of MPTP, a chemical known to cause the destruction of dopaminergic neurons in the nigrostriatal tract... 

Singer TP, Ramsay RR. Mechanism of neurotoxicity of MPTP. FEBS Lett 1990 274 1-8. 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

RESPONSE We do not understand all there is to know about the mechanisms of MPTP neurotoxicity, but it seems to involve MPP+, which is potentially cytotoxic to all cells but that attains toxic concentrations after MPTP administration only in cells that concentrate MPP+. Dopamine apparently is not involved in the neurotoxic effects of MPTP. I am attracted to the idea that dopamine itself may be involved in the etiology of Parkinson s disease, that dopamine neurons may be at risk because of the nature of their neurotransmitter. 

MPTP decreases glutathione levels and increases the levels of reactive oxygen species and the degree of lipid peroxidation in mouse brain slices in vitro and increases the levels of reactive oxygen species in mouse brain in vivo. MPTP neurotoxicity in vitro is reduced by glutathione. In vitro studies have shown that MPP neurotoxicity can be reduced by vitamin E, vitamin C, coenzyme Q, and mannitol (but not by superoxide dismutase, catalase, allopurinol, or dimethyl sulfoxide). P-Carotene, vitamin C, and /V-acctylcystcine partially protect against the neurotoxic effects of MPTP in mice, as do nicotinamide, coenzyme Q, and the free-radical spin trap A-tert-butyl-a-(sulfophenyl) nitrone. 

Heikkila RE, Hess A, Duvoisin RC (1984) Dopaminergic neurotoxicity of l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine (MPTP) in mice. Science 224 1451-1453. 

Heikkila RE, Duvoisin RC, Finberg JP, Youdim MBH (1985a) Prevention of MPTP-induced neurotoxicity by AGN-1133 and AGN-1135, selective inhibitors of monoamine oxidase-B. Eur J Pharmacol 776 313-317. 

Singer, T.P., Ramsay, R.R., McKeown, K., Trevor, A., Castagnoli, N.E., Jr. (1988). Mechanism of the neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+), the toxic bioactivation product of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP). Toxicology 49 17-23. 

Similarly, a crucial role of DAT in the neurotoxic action of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been supported in mice lacking DAT (62,63). In numerous previous studies it had been demonstrated that MPTP neurotoxicity involves selective uptake of its active metabolite, l-methyl-4-phenylpyridinium (MPP+) into the DA neuron via the DAT (6,9). In DAT-KO mice treated with MPTP, markers of striatal neurotoxicity, such as depletion in DA levels and reactive astrogliosis, were virtually absent, whereas in DAT heterozygotes a partial sensitivity was observed (62). In another investigation, no apparent DA cell body loss was found in the substantia nigra of MPTP-treated DAT-KO mice (63). Thus, an absolute requirement of DAT for development of MPTP toxicity in vivo has been firmly established (9,62,63). 

Blum D, Torch S, Lambeng N,Nissou M, Benabid AL, et al. 2001. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP contribution to the apoptotic theory in Parkinson s disease. Prog. Neurobiol. 65 135-72... 

The critical question concerns the neurotoxic potential of HP in the human. Since the development of drug induced tardive dyskinesias often requires months or even years of drug exposure (Gerlach and Casey 1988 Casey 1991), the demonstration of toxin-induced lesions in experimental animals may be difficult. Furthermore, in view of the dramatic species selectivity of MPTP (Singer et al. 1987 Giovanni et al. 1994a, 19946), the absence of a detectable anatomical lesion in HP- or HPTP-treated rodents may not provide a definitive answer to the question... 

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