Skip to main content
Log in

Some features of the nigrostriatal dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse

  • Original Articles
  • Published:
Molecular and Chemical Neuropathology

Conclusion

The discovery that a rather simple chemical substance can produce such a highly selective neuronal degeneration in the substantia nigra, the brain area most affected in Parkinson’s disease, has resulted in a vast amount of research with MPTP. We and others have hoped that by gaining an understanding of its mechanism of action, we might come closer to discovering the cause(s) of idiopathic Parkinson’s disease. Indeed, we have learned some fascinating things regarding the roles of monoamine oxidase B and the dopamine transport system in mediating the actions of MPTP. It is clear that the MPTP-treated mouse is a good model for Parkinson’s disease. As such, it may help to define the role of dopamine deficiency in the pathophysiology of Parkinson’s disease as well as provide a model in which potential anti-Parkinsonian therapeutic agents can be tested.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ballard P. A., Tetrud J. W., and Langston J. W. (1985) Permanent human Parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): Seven cases.Neurology 5, 949–956.

    Google Scholar 

  • Bankiewicz K. S., Oldfield, E. H., Chiueh C. C., Doppman J. L., Jacobowitz D. M., and Kopin I. J. (1986) Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).Life Sci. 39, 7–16.

    Article  PubMed  CAS  Google Scholar 

  • 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 byN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Proc. Natl. Acad. Sci. USA 80, 4546–4550.

    Article  PubMed  CAS  Google Scholar 

  • Burns R. S., Phillips J. M., Chiueh C. C., and Parisi J. E. (1986) The MPTP-treated monkey model of Parkinson’s disease,MPTP:A Neurotoxin Producing a Parkinsonian Syndrome (Markey S. P., Castagnoli N., Jr., Trevor A. J., and Kopin I. J., eds.), pp. 23–42, Academic, Orlando, FL.

    Google Scholar 

  • Calne D. B. Langston J. W., Martin W. R. W., Stoessi A. J., Ruth T. J., Adam M. J., Pate B. D., and Schulzer, M. (1985) Positron emission tomography after MPTP: observations relating to the cause of Parkinson’s disease.Nature 317, 246–248.

    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 

  • Chiueh C. C., Markey S. P., Burns R. S., Johannessen J. N., Pert A., and Kopin I. J. (1984) Neurochemical and behavioral effects of systemic and intranigral administration ofN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the rat.Eur. J. Pharmacol. 100, 189–194.

    Article  PubMed  CAS  Google Scholar 

  • Davis G. C., Williams A. C., Markey S. P., Ebert M. H. Caine E. D., Reichert C. M., and Kopin I. J. (1979) Chronic Parkinsonian secondary to intravenous injection of meperidine analogues.Psychiatry Res. 1, 249–254.

    Article  PubMed  CAS  Google Scholar 

  • D’Amato R. J., Lipman Z. P., and Snyder S. H. (1986) Selectivity of the Parkinsonian neurotoxin MPTP: Toxic metabolite MPP+ binds to neuromelanin.Science 231, 987–989.

    Article  PubMed  Google Scholar 

  • Donnan G. A., Kaczmarczyk S. J., McKenzie J. S., Rowe P. J., Kalnins R. M., and Mendelsohn F. A. O. (1987) Regional and temporal effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on dopamine uptake sites in mouse brain.J. Neuro. Sci. 81, 261–271.

    Article  CAS  Google Scholar 

  • Forno L. S., Langston J. W., DeLanney L. E., Irwin I., and Ricaurte G. A. (1986) Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys.Ann. Neurol. 20, 449–455.

    Article  PubMed  CAS  Google Scholar 

  • Forno L. S., Langston J. W., DeLanney L. E., and Irwin I. (1988) An electron microscopic study of MPTP-induced inclusion bodies in an old monkey.Brain Res. 448, 150–157.

    Article  PubMed  CAS  Google Scholar 

  • Fuller R. W. and Hemrick-Luecke S. K. (1985) Mechanism 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 

  • German D. C., Dubach M., Askari S., Speciale S. G., and Bowden D. M. (1988) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonian syndrome in Macaca Fascicularis: which midbrain dopaminergic neurons are lost?Neuroscience 24, 161–174.

    Article  PubMed  CAS  Google Scholar 

  • Gibb W. R. G., Lees A. J., Jenner P., and Marsden C. D. (1986) Effects of MPTP in the midbrain of the marmoset,MPTP:A Neurotoxin Producing a Parkinsonian Syndrome (Markey S. P., Castagnoli N., Jr., Trevor A. J., and Kopin I. J., eds.), pp. 607–614, Academic, Orlando, FL.

    Google Scholar 

  • Gupta M., Felten D. L., and Gash D. M. (1984) MPTP alters central catecholamine neurons in addition to the nigrostriatal system.J. Neurochem. 44, 117–127.

    Google Scholar 

  • Gupta M., Gupta B. K., Bruemmer V., Sladek J. R., and Felten D. L. (1986) Aged mice are more sensitive to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment than young adults.Neurosci. Lett. 70, 326–331.

    Article  PubMed  CAS  Google Scholar 

  • Hadjiconstantinou M., Cavalla D., Anthoupoulou E., Laird H. E., and Neff N. H. (1985)N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine increases acetylcholine and decreases dopamine in mouse striatum: Both responses are blocked by anticholinergic drugs.J. Neurochem. 45, 1957–1959.

    Article  PubMed  CAS  Google Scholar 

  • Heikkila R. E. (1985) Differential neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Swiss-Webster mice from diffent sources.Eur. J. Pharmacol. 117, 131–133.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    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-phenyls-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors.Nature 311, 467–469.

    Article  PubMed  CAS  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 by dopamine neurons explains selective toxicity.Proc. Natl. Acad. Sci. USA 82, 2173–2177.

    Article  PubMed  CAS  Google Scholar 

  • Jenner P., Rupniak N. M. J., Rose S., Kelly E., Kilpatrick G., Lees A., and Marsden C. D. (1984) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in the common marmoset.Neurosci. Lett. 50, 85–90.

    Article  PubMed  CAS  Google Scholar 

  • Jonsson G., Sundstrom E., Mefford I., Olson I., Johnson S., Freedman R., and Hoffer B. (1985) Electrophysiological and neurochemical correlates of the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse.Naunyn Schmiedeberg’s Arch. Pharmacol. 331, 1–6.

    Article  CAS  Google Scholar 

  • Kalaria R. N., and Harik S. I. (1987) Blood-brain barrier monoamine oxidase: Enzyme characterization of cerebral microvessels and other tissues from six mammalian species, including human.J. Neurochem. 49, 856–864.

    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-analog synthesis.Science 219, 979–980.

    Article  PubMed  CAS  Google Scholar 

  • Langston J. W., Forno L. S., Rebert C. S., and Irwin I. (1984) Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) in squirrel monkey.Brain Res. 292, 390–394.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Mayer R. A., Walters A. S., and Heikkila R. E. (1986) 1-methyl-4-phenyl-1,2,3,6-tetrahydropridine (MPTP) administration to C57-black mice leads to parallel decrements in neostriatal dopamine content and tyrosine hydroxylase activity.Eur. J. Pharmacol. 120, 375–377.

    Article  PubMed  CAS  Google Scholar 

  • Melamed E., Rosenthal J., Globus M., Cohen O., Frucht Y., and Uzzan A. (1985) Mesolimbic dopaminergic neurons are not spared by MPTP neurotoxicity in mice.Eur. J. Pharmacol. 114, 97–100.

    Article  PubMed  CAS  Google Scholar 

  • Mitchell I. J., Cross A. J., Sambrook M. A., and Crossman A. R. (1985) Sites of the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the macaque monkey include the ventral tegmental area and the locus coeruleus.Neurosci. Lett. 61, 195–200.

    Article  PubMed  CAS  Google Scholar 

  • Nicklas W. J., Vyas I., and Heikkila R. E. (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenylpyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.Life Sci. 36, 2503–2508.

    Article  PubMed  CAS  Google Scholar 

  • Nicklas W. J., Youngster S. K., Kindt M. V., and Heikkila R. E. (1987) MPTP, MPP+ and mitochondrial function.Life Sci. 40, 721–729.

    Article  PubMed  CAS  Google Scholar 

  • Parisi J. E. and Burns R. S. (1986) The neuropathology of MPTP-induced Parkinsonism in man and experimental animals,MPTP:A Neurotoxin Producing a Parkinsonian Syndrome (Marke S. P., Castagnoli N., Jr., Trevor A. J., and Kopin I. J., eds), pp. 141–148, Academic, Orlando, FL.

    Google Scholar 

  • Pileblad E. and Carlsson A. (1985) Catecholamine-uptake inhibitors prevent the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mouse brain.Neuropharmacology 24, 689–692.

    Article  PubMed  CAS  Google Scholar 

  • Ramsay R. R., Salach J. I., and Singer T. P. (1986) Uptake of the neurotoxin 1-methyl-4-phenylpyridine (MPP+) by mitochondria and its relation to the inhibition of the mitochondrial oxidation of NAD-linked substrates by MPP+.Biochem. Biophys. Res. Commun. 134, 743–748.

    Article  PubMed  CAS  Google Scholar 

  • Riachi N. J. and Harik S. I. (1988) Strain differences in systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in mice correlate best with monoamine oxidase activity at the blood-brain barrier.Life Sci. 42, 2359–2363.

    Article  PubMed  CAS  Google Scholar 

  • Ricaurte G. A., DeLanney L. E., Irwin I., and Langston J. W. (1987a) Older dopaminergic neurons do not recover from the effects of MPTP.Neuropharmacology 26, 97–99.

    Article  PubMed  CAS  Google Scholar 

  • Ricaurte G. A., Irwin I., Forno L. S., DeLanney L. E., Langston E., and Langston J. W. (1987b) Aging and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of dopaminergic neurons in the substantia nigra.Brain Res. 403, 43–51

    Article  PubMed  CAS  Google Scholar 

  • Sayre L. M., Arora P. K., Feke S. C., and Urbach F. L. (1986) Mechanism of induction of Parkinson’s disease by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Chemical and electrochemical characterization of a geminaldimethyl-blocked analogue of a postulated toxic metabolite.J. Am. Chem. Soc. 108, 2464–2466.

    Article  CAS  Google Scholar 

  • Schneider J. S. and Denaro F. J. (1988) Astrocytic responses to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).J. Neuropathol. Exp. Neurol. 47, 452–458.

    Article  PubMed  CAS  Google Scholar 

  • Schneider J. S., Yuwiler A., and Markham C. H. (1986) Production of a Parkinson-like syndrome in the cat withN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): Behavior, histology, and biochemistry.Exptl. Neurol. 91, 293–307.

    Article  CAS  Google Scholar 

  • Schneider J. S., Yuwiler A., and Markham C. H. (1987) Selective loss of subpopulations of ventral mesencephalic dopaminergic neurons in the monkey following exposure to MPTP.Brain Res. 411, 144–150.

    Article  PubMed  CAS  Google Scholar 

  • Sershen H., Mason M. F., Hashim A., and Lajtha A. (1985) Effect ofN-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on age related changes in dopamine turnover and transporter function in the mouse striatum.Eur. J. Pharmacol. 113, 135–136.

    Article  PubMed  CAS  Google Scholar 

  • Singer T. P., Castagnoli N., Jr., Ramsay, R. R., and Trevor A. J. (1987) Biochemical events in the development of Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.J. Neurochem. 49, 1–8.

    Article  PubMed  CAS  Google Scholar 

  • Snyder S. H. and D’Amato R. J. (1986) MPTP: A neurotoxin relevant to the pathophysiology of Parkinson’s disease.Neurology 36, 250–258.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sonsalla P. K., Youngster S. K., Kindt M. V., and Heikkila R. E. (1987) Characteristics of 1-methyl-4-(2′-Methylphenyl)-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the mouse.J. Pharmacol. Exp. Ther. 242. 850–857.

    PubMed  CAS  Google Scholar 

  • Sundstrom E. and Jonsson G. (1985) Pharmacological intereference with the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse.Eur. J. Pharmacol. 110, 293–299.

    Article  PubMed  CAS  Google Scholar 

  • Sundstrom E., Stromberg I., Tsutsumi T., Olson L., and Jonsson G. (1987) Studies on the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57/BL/6 mice. Comparison with three other strains of mice.Brain Res. 405, 26–38.

    Article  PubMed  CAS  Google Scholar 

  • Switzer R. C., III (1985) Argyrophilic degeneration of substantia nigra in C57 mice due to 1-methyl-4-phenyl-1,2,5,6-tetrahyropyridine (MPTP).Neurosci. Abst. 11, 992.

    Google Scholar 

  • Westlund K. N., Denney R. M., Rose R. M., and Abell C. W. (1988) Localization of distinct monoamine oxidase B cell populations in human brainstem.Neuroscience 25, 439–456.

    Article  PubMed  CAS  Google Scholar 

  • Youngster S. K., Duvoisin R. C., Hess A., Sonsalla P. K., Kindt M. V., and Heikkila R. E. (1986) 1-Methyl-4-(2′ methylphenyl)-1,2,3,6-tetrahydro-pyridine (2′CH3-MPTP), is a more potent dopaminergic neurotoxin than MPTP in mice.Eur. J. Pharmacol. 122, 283–287.

    Article  PubMed  CAS  Google Scholar 

  • Youngster S. K., Sonsalla P. K., and Heikkila R. E. (1987) Evaluation of the biological activity of several analogs of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.J. Neurochem. 48, 929–934.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heikkila, R.E., Sieber, BA., Manzino, L. et al. Some features of the nigrostriatal dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse. Molecular and Chemical Neuropathology 10, 171–183 (1989). https://doi.org/10.1007/BF03159727

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03159727

Keywords

Navigation