Summary
Administration of MPTP (1-methyl-1,2,3,6-tetrahydropyridine) to Macaca fascicularis monkeys produced severe parkinsonism (hypokinesia, tremor, rigidity, aphagia, adipsia) and more than 90% loss of nigral dopamine neurons, striatal dopamine content and striatal 3H-mazindol binding. Treatment with the catecholamine uptake blocker nomifensine counteracted the behavioral, histological and neurochemical effects induced by MPTP. For obtaining best protection, nomifensine had to be administered for weeks after MPTP. The results suggest that the selective target-directed neurotoxic action of MPTP on dopamine neurons in monkeys is mediated via the dopamine uptake mechanism.
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Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (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 (USA) 80: 4546–4550
Chiba K, Trevor A, Castagnoli Jr N (1984) Metabolism of the neurotoxic tertiary amine MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 120: 574–578
Cohen G, Pasik P, Cohen B, Leist A, Mytilineou C, Yahr MD (1984) Pargyline and deprenyl prevent the neurotoxicity of l-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) in monkeys. Eur J Pharmacol 106: 209–210
Davis CG, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, Kopin IJ (1979) Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiat Res 1: 249–254
Felten DL, Sladek JR (1983) Monoamine distribution in primate brain. V. Monoaminergic nuclei: anatomy, pathways and local organization. Brain Res Bull 10: 171–284
Garver DL, Sladek JR (1975) Monoamine distribution in primate brain. I. Catecholamine-containing perikarya in the brainstem of Macaca speciosa. J Comp Neurol 159: 289–304
Hallman H, Sundström E, Jonsson G (1984) Effects of the noradrenaline neurotoxin DSP4 on monoamine neurons and their transmitter turnover in CNS. J Neural Transm 60: 89–102
Heikkila RE, Manzino L, Cabbat FC, Duvoisin RC (1984) Inhibition of monoamine oxidase produces protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Nature 311: 467–469
Hunt P, Kannengiesser MH, Raynaud JP (1974) Nomifensine: a new potent inhibitor of dopamine uptake into synaptosomes from rat brain striatum. J Pharm Pharmacol 26: 370–371
Javitch JA, Blaustein RO, Snyder SH (1984) 3H-mazindol binding associated with neuronal dopamine and norepinephrine uptake sites. Mol Pharmacol 26: 35–44
Javitch JA, D'Amato RJ, Strittmatter SM, Snyder SN (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 (USA) 82: 2173–2177
Johannessen JN, Chiueh CC, Burns RS, Markey SP (1985) Differences in the metabolism of MPTP in the rodent and primate parallel differences in sensitivity to its neurotoxic effects. Life Sci 36: 219–224
Jonsson G, Hallman H, Mefford I, Adams RN (1980) The use of liquid chromatography with electrochemical detection for the determination of adrenaline and other biogenic monoamines in the CNS. In: Fuxe K, Goldstein M. Hökfelt B, Hökfelt T (eds) Central adrenaline neurons. Pergamon Press, Oxford, New York, pp 59–71
Jonsson G, Sundström E, Nwanze E, Hallman H, Luthman J (1986) Mode of action of MPTP on catecholaminergic neurons in the mouse. In: Markey SP, Castagnoli Jr N, Trevor AJ, Kopin IJ (eds) MPTP — a neurotoxin producing parkinsonian syndrome. Academic Press, New York (in press)
Langston JW, Ballard P, Tetrud JW, Kopin IJ (1983) Chronic parkinsonism in humans due to a product of meperidineanalog synthesis. Science 219: 979–980
Langston JW, Irwin I, Langston EB, Forno LS (1984) Pargyline prevents MPTP-induced parkinsonism in primates. Science 225: 1480–1482
Markey SP, Johannessen JN, Chiueh CC, Burns RS, Herkenham MA (1984) Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism. Nature 311: 464–467
Melamed E, Rosenthal J, Globus M, Cohen O, Uzzan A (1985) Suppression of MPTP-induced dopaminergic toxicity in mice by nomifensine and L-DOPA. Brain Res 342: 401–404
Schultz W, Studer A, Jonsson G, Sundström E, Mefford I (1985) Deficits in behavioural initiation and execution processes in monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism. Neurosci Lett 59: 225–232
Schütz E (1977) Toxikologische Prüfung von Nomifensin. In: Lindenlaub E (ed) Alival (Nomifensine). Schattauer, Stuttgart, pp 105–109
Sundström E, Jonsson G (1985) Pharmacological interference with the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine (MPTP) on central catecholamine neurons in the mouse. Eur J Pharmacol 110: 293–299
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Schultz, W., Scarnati, E., Sundström, E. et al. The catecholamine uptake blocker nomifensine protects against MPTP-induced parkinsonism in monkeys. Exp Brain Res 63, 216–220 (1986). https://doi.org/10.1007/BF00235666
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DOI: https://doi.org/10.1007/BF00235666