Abstract
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to produce a Parkinsonian syndrome in man (Davis et al., 1979; Langston et al., 1983) and to destroy the nigrostriatal dopaminergic pathway in monkeys (Burns et al., 1983; Langston et al., 1984a) and mice (Heikkila et al., 1984a; Hallman et al., 1985). The discovery that administration of such a simple chemical substance can reproduce the behavioral and pathological symptoms of Parkinson’s disease has led some investigators to suggest that idiopathic Parkinson’s disease may be caused by a compound present either in the environment or as an endogenous biological constituent (Snyder and D’Amato, 1986). Searches have been conducted for compounds structurally similar to MPTP which might be responsible for producing idiopathic Parkinson’s disease and thousands of compounds, either synthesized in the laboratory or isolated from natural sources, have been identified which share certain structural features with MPTP (Markey and Schmuff, 1986). Our laboratory has been involved in the synthesis and evaluation of the neurotoxic potential of numerous analogs of MPTP with the intent of defining the structural requirements for production of MPTP-like neurotoxicity so that we will be able to predict the likelihood that any particular compound will be an MPTP-like neurotoxin.
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References
Burns, R.S., C.C. Chiueh, S.P. Markey, M.H Ebert, D.M. Jacobowitz and I.J. Kopin, 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.
Bradbury, A.J., Costall, B., Domeney, A.M., Jenner, P., Kelly, M.E., Marsden, C.D, andNaylor, R.J., 1986, MPP + is neurotoxic to the nigrostriatal dopamine pathway, Nature 319:56–7
Chiba, K., Petersen, K.P., Castagnoli, K.P., Trevor, A.J., and Castagnoli, N. Jr., 1985, Studies on the molecular mechanism of bioactivation of the selective nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine, Drug Metab. Disp. 13:342–347
Chiba, K. A., Trevor, A.J., and Castagnoi, N. Jr., 1984, Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase, Biochem. Biophys. Res. Commun. 120:674–578.
David, G.C., Williams, A.C., Markey., S.P., Ebert, M.H., Caine, E.D, Reichert, C.M., and Kopin, I.J, 1979, Chronic parkinsonism secondary to intravenous injection of meperidine analogues, Psychiatry Res. 1:249–254.
Fries, D.S, Vries, J.D., Hazelhoff, B., and Horn, A.S., 1986, Synthesis and toxicity toward nigrostriatal dopamine neurons of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analogues, J. Med. Chem. 29:424–427.
Gessner, W., Brossi, A., Shen, R., and Abell, C.W., 1985, Further insight into the mode of action of the neurotoxin 1-methyl-4-phenyl/1,2,3,6-tetrahydropyridine (MPTP), FEBS Lett. 183:345–348.
Hallman, H., Lange, J., Olson, L., Stromberg, I. and Jonsson, G. 1985, Neurochemical and histochemical characterization of neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on brain catechalamine neurons in the mouse, J. Neurochem. 44:117–127.
Heikkila, R.E., Hess, A., and Duvoisin, R.C., 1984a, Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, Science, 224: 1451–1453.
Heikkila, R.E., Kindt, M.V. Sonsalla, P.K. Giovanni, A., Youngster S.K., McKeown, K.A. and Singer, T.P. in press, Proc. Natl. Acad. Sci., U.S.A.
Heikkila, R.E., Manzino, L., Cabbat, F.S., and Duvoisin, R.C., 1984b, Protection against the dopaminergic neurotoxicity of 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine by monoamine oxidase inhibitors, Nature 311:467–469
Heikkila, R.E., Nicklas, W.J., and Duvoisin, R.C., 1985, Dopaminergic toxicity after the stereotaxic administration of the 1-methyl-4-phenylpyridinium ion (MPP +) to rats, Neurosci. Lett. 59:135–140.
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 dopaine neurons explains selective toxicity, Proc. Natl. Acad. Sci., U.S.A. 82:2173–2177.
Kindt, M.V., Heikkila, R.E., and Nicklas, W.J., 1987, Mitochondrial and metabolic toxicity of l-metyl-4-(2′methylphenyl)-1,2,3,6-tetrahydropyridine, J. Pharmacol. Exp. Ther. 242:858–863.
Kindt, M.V. Youngster, S.K. Sonsalla, P.K., Duvoisin, R.C., and Heikkila, R.E., in press Role for monoamine oxidase-A (MAO-A) in the bioactivation and nigrostriatal dopaminergic neurotoxicity of the MPTP analog, 2′Me-MPTP, Eur. J. Pharmacol.
Langston, J.W., Ballard, P., Tetrud, J.W., and Irwin, I. 1983, Chronic parkinsonism in humans due to a product of meperidine-analog synthesis, Science 219:979–980.
Langston, J.W., Forao, 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.
Langston, J.W., Irwin, I., Langston, E.B., and Forno, L.S., 1984b, Pargylineprevents MPTP-inducedparkinsonism in primates, Science 225:1480–1482.
Lewin R., 1985, Clinical trials for Parkinson’s disease? Science 230:527.
Markey, S.P., Johannessen, J.N., Chiueh, C.C., Burns, R.S., and Herkenham, M.A., 1984, Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism, Nature 311:464–467.
Markey, S.P. and Schmuff, N.R., 1986, The pharmacology of the parkinsonian syndrome producing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and structurally related compounds, Med. Res. Rev. 6:386–429.
Mayer, R.A., Kindt, M.V., and Heikkila, R.E., 1986, Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport, J. Neurochem, 47:1073–1079.
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
Nicklas, W.J. Vyas, I., and Heikkila, R.E., 1985, Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenylpridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahyd-ropyridine, Life Sci. 36, 2503–2508.
Nicklas, W.J., Younster, S.K., Kindt, M.V., and Heikkila, R.E., 1986, MPTP, MPP+, and mitochondrial function, Life Sci 40:721–729.
Ramsay, R.R., Salach, J.I., Dadgar, J. and Singer, T.P. 1986, Inhibition of mitrochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism, Biochem. Biophys. Res. Commun. 135:743–748.
Snyder, S.H. and D’ Amato, 1986, MPTP, a neurotoxin relevant to the pathophysiology of Parkinson’s disease, Neurology 36:250–258.
Sonsalla, P.K., Youngster, S.K., Kindt, M.V., and Heikkila, R.E., 1987, Characteristics of 1-methyl-4-(2′-methylphenyl)-l,2,3,6-tetrahydropyridine-induced neurotoxicity in the mouse, J. Pharmacol. Exp. Ther. 242:850–857.
Vyas, I., Heikkilla, R.E., and Nicklas, W.J., 1986, Studies on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Inhibition of NAD-linked substrate oxidation by its metabolite, 1-methyl-4-phenyl-pyridinium, J. Neurochem. 46:1501–1507.
Youngster, S.K., Duvoisin, R.C., Hess, A., Sonsalla, P.K., Kindt, M.V., andHeikikila, R.E., 1986,1-Methyl-4-(2′-methyphenyl)-l,2,3,6-tetrahydropyridine (2′Me-MPTP) is a more potent dopaminergic neurotoxin than MPTP in mice, Eur. J. Pharmacol. 122:283–287.
Youngster, S.K., Sonsalla, P.K., and Heikkila, R.E., 1987, Evaluation of the biological activity of several analogs of the dopaminergic neurotoxin MPTP, J. Neurochem. 48:929–934
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© 1988 Plenum Press, New York
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Younster, S.K., Heikkila, R.E. (1988). A Biological Evaluation Of Some 2′-Substituted Analogs Of MPTP. In: Hefti, F., Weiner, W.J. (eds) Progress in Parkinson Research. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0759-4_14
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DOI: https://doi.org/10.1007/978-1-4613-0759-4_14
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