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Studies on the Toxicity of MPTP to Dopamine Neurons in Tissue and Cell Cultures

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Abstract

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin with high specificity for the dopamine (DA) neurons of the nigrostriatal pathway of humans (Davis et al., 1979), monkeys (Burns et al., 1983) and mice (Heikkila et al., 1984a). In humans, the lesion which results from MPTP toxicity produces symptoms similar to idiopathic parkinsonism (Langston et al., 1983). The etiology of idiopathic parkinsonism remains still unknown and it is hoped that study of MPTP induced parkinsonism can elucidate the causes of this disease. Although it is possible that idiopathic parkinsonism bears no relationship with MPTP intoxication, knowledge of the cellular and molecular events that occur during MPTP induced neuronal degeneration would be a significant contribution to our understanding of neuronal susceptibility to environmental and/or endogenous neurotoxins.

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References

  • Burns, R. S., Chiueh, C. C., Markey, S. P., Ebert, M. H., Jacobowitz, D. M. and Kopin, I. J. (1983) 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. Proc. Natl. Acad. Sci. U.S.A., 80:4546–4550.

    Article  PubMed  CAS  Google Scholar 

  • Castagnoli, N., Chiba, K. and Trevor, A.J. (1985) Potential bioactivation pathways for the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Life Sci. 36:225–230.

    Article  PubMed  CAS  Google Scholar 

  • Chiba, K., Trevor, A. and Castagnoli, N., Jr. (1984) Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem. Biophys. Res. Commun. 120:574–578.

    Article  PubMed  CAS  Google Scholar 

  • Chiba, K., Trevor, A.J. and Castagnoli, N., Jr. (1985) Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes. Biochem. Biophys. Res. Commun. 128:1228–1232, 1985.

    Article  PubMed  CAS  Google Scholar 

  • Cohen, G., Pasik, P.,.Cohen, B., Leist, A., Mytilineou, C. and Yahr, M. D. (1984) Pargyline and deprenyl prevent the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys. Eur. J. Pharmacol., 106:209–210.

    Article  PubMed  CAS  Google Scholar 

  • Cohen, G. and Mytilineou, C. (1985) Studies on the mechanism of action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Life Sci. 36:237–242.

    Article  PubMed  CAS  Google Scholar 

  • Davis, G.C., Williams, A.C., Markey, S.P., Ebert, M.H., Jacobowitz, D.M. and Kopin, I.J. (1979) Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiat. Res. 1:249–254.

    Article  CAS  Google Scholar 

  • Friedman, L. and Mytilineou, C. (1987) The toxicity of MPTP to dopamine neurons in culture is reduced at high concentrations. Neurosci. Lett. 79:65–72.

    Article  PubMed  CAS  Google Scholar 

  • Fuller, R. and Hemrick-Luecke, S.K. (1985) Mechanisms of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity to striatal dopamine neurons in mice. Prog. Neuro-Psychopharmacol. Biol. Psychiat. 9:687–690.

    Article  CAS  Google Scholar 

  • Glover, V., Gibb, C. and Sandler, M. (1986) Monoamine oxidase B (MAO-B) is the major catalyst for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) oxidation in human brain and other tissues. Neurosci. Lett. 64:216–220.

    Article  PubMed  CAS  Google Scholar 

  • Heikkila, R. E., Hess, A. and Duvoisin, R. (1984a) Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine in mice. Science, 224:1451–1453.

    Article  PubMed  CAS  Google Scholar 

  • Heikkila, R. E., Manzino. L., Cabbat, F. S. and Duvoisin, R. C. (1984b) Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature, 311: 467–469.

    Article  PubMed  CAS  Google Scholar 

  • Irwin, I. (1986) The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): A key to Parkinson’s disease? Pharmaceut. Res. 3:7–11, 1986.

    Article  CAS  Google Scholar 

  • Javitch, J.A. and Snyder, S.H. (1985) Uptake of MPP (+) by dopamine neurons explains selectivity of parkin-sonism-inducing neurotoxin, MPTP. Eur. J. Pharmacol. 106:445–456.

    Google Scholar 

  • Javitch, J. A., D’Amato, R. J., Strittmatter, S. M. and Snyder, S. H. (1985) Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: Uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc. Natl. Acad. Sci. U.S.A., 82:2173–2177.

    Article  PubMed  CAS  Google Scholar 

  • Johannessen, J.N., Adams, J.D., Schuller, H.M., Bacon, J.P. and Markey, S.P. (1986) 1-methyl-4-phenyl-pyridine (MPP +) induces oxidative stress in the rodent. Life Sci. 38:743–749.

    Article  PubMed  CAS  Google Scholar 

  • Langston, J. W., Ballard, P, Tetrud, J. W. and Irwin, I. (1983) Chronic parkinsonism in humans due to a product of meperidine-analogue synthesis. Science 219:979–980.

    Article  PubMed  CAS  Google Scholar 

  • Langston, J.W., Forno, L.S., Rebert, C.S. and Irwin, I. (1984a) Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the squirrel monkey. Brain Res. 292: 390–394.

    Article  PubMed  CAS  Google Scholar 

  • Langston, J. W., Irwin, I., Langston, E. B. and Forno, L. S. (1984b) Pargyline prevents MPTP-induced parkinsonism in primates. Science, 225, 1480–1482.

    Article  PubMed  CAS  Google Scholar 

  • Martinovits, G., Melamed, E., Cohen, 0., Rosenthal, J. andUzzan, A. (1986) Systemic administration of antioxidants does not protect mice against the dopaminergic neurotoxicity of methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurosci. Lett. 69:192–197.

    Article  PubMed  CAS  Google Scholar 

  • Mytilineou, C. (1987) Tissue culture studies of aging in the nervous system: toxicity of MPTP to dopamine neurons. In Vernadakis, A. (ed.), “Model Systems of Development and Aging of the Nervous System”, pp. 491–500, Martinus Nijhoff.

    Chapter  Google Scholar 

  • Mytilineou, C. and Cohen, G. (1984) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine destroys dopamine neurons in explants of rat embryo mesencephalon. Science, 225:529–531.

    Article  PubMed  CAS  Google Scholar 

  • Mytilineou, C., Cohen, G. and Heikkila, R. E. (1985) 1-methyl-4-phenylpyridine (MPP +) is toxic to mesencephalic dopamine neurons in culture. Neurosci. Lett. 57:19–24.

    Article  PubMed  CAS  Google Scholar 

  • Perry, T.L., Yong, V. W., Clavier, R.M., Jones, K., Wright, J.M., Foulks, J.G. and Wall, R. A. (1985) Partial protection from the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by four different antioxidants in the mouse. Neurosci. Lett. 60:109–114.

    Article  PubMed  CAS  Google Scholar 

  • Sachs, Ch., Jonsson,.G., Heikkila, R. and Cohen, G. (1975) Control of the neurotoxicity of 6-hydroxydopamine by intraneuronal noradrenaline in rat iris. Acta Physiol. Scand. 93:345–351.

    Article  PubMed  CAS  Google Scholar 

  • Salach, J.I., Singer, T.P., Castagnoli, N. and Trevor, A. (1984) Oxidation of the neurotoxic amine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by monoamine oxidases A and B and suicide inactivation of the enzymes by MPTP. Biochem. Biophys. Res. Commun. 125:831–835.

    Article  PubMed  CAS  Google Scholar 

  • SanchezRamos, J.R., Barrett, J.N., Goldstein, M., Weiner, W.J. and Hefti, F. (1986) 1-methyl-4-phenyl-pyridinium (MPP+) but not 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) selectively destroys dopaminergic neurons in cultures of dissociated rat mesencephalic neurons. Neurosci. Lett., 72:215–220.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt, C. J., Bruckwick, E. and Lovenberg, W. (1985) Lack of evidence supporting a role for dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity. Eur. J. Pharmacol. 113:149–150.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt, C.J., Ritter, J.K., Sonsalla, P.K., Hanson, G.R. and Gibb, J.W. (1985) The role of dopamine in the neurotoxic effects of methamphetamine. J. Pharmacol. Exp. Ther. 233:539–544.

    PubMed  CAS  Google Scholar 

  • Singer, T.P., Salach, J.I. and Crabtree, D. (1985) Reversible inhibition and mechanism-based irreversible inactivation of monoamine oxidases by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Biochem. Biophys. Res. Comm. 127:707–712.

    Article  CAS  Google Scholar 

  • Sonsalla, P.K. and Heikkila, R.E. (1986) The influence of dose and dosing interval on MPTP induced dopaminergic neurotoxicity. Eur. J. Pharmacol. 129:339–345.

    Article  PubMed  CAS  Google Scholar 

  • Tipton, K.F., McCrodden, J.M. and Youdim, M.B.H. (1986) Oxidation and enzyme-activated irreversible inhibition of rat liver monoamine oxidase-B by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Biochem. J. 240:379–383.

    PubMed  CAS  Google Scholar 

  • Youdim, M.B.H. (1975) Assay and purification of brain monoamine oxidase. In "Research methods in Neurobiology" Vol. 3, p.p. 167–207 (Marks, N. Rodnight, R. Eds.) New York, Plenum.

    Google Scholar 

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© 1988 Plenum Press, New York

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Mytilineou, C., Friedman, L.K., Danias, P. (1988). Studies on the Toxicity of MPTP to Dopamine Neurons in Tissue and Cell Cultures. In: Hefti, F., Weiner, W.J. (eds) Progress in Parkinson Research. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0759-4_16

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  • DOI: https://doi.org/10.1007/978-1-4613-0759-4_16

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4612-8068-2

  • Online ISBN: 978-1-4613-0759-4

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