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Toxicity of Structural Analogs of 1-methyl-4-Phenyl Pyridinium (MPP+) and Related Compounds on Dopaminergic Neurons in Culture

  • Franz Hefti
  • Juan R. Sanchez-Ramos
  • Patrick P. Michel
  • Simon Efange
  • Berton C. Pressman
Chapter
  • 91 Downloads

Abstract

MPTP selectively destroys the nigrostriatal dopaminergic neurons in primates and the mouse and produces a neuropathological lesion in the primate similar to that seen in idiopathic Parkinson’s disease (Heikkila, 1984: Langston, 1985; Langston et al., 1983). These findings led to the speculation that environmental toxins may cause idopathic Parkinson’s disease. According to this hypothesis, exposure to a neurotoxin during a short period of time may reduce the number of dopaminergic neurons, so that an age-related slow degeneration of these cells will reduce, at an earlier time, the number of surviving cells to a level insufficient to support normal function. Alternatively, it is possible that long-term exposure to small quantities of a neurotoxin might produce similar effects as short-term exposure to high levels and gradually result in the appearance of clinical symptoms. At present, no chemical has been identified which could be responsible for causing idiopathic Parkinson’s disease. However, in the modern industrial society, humans are exposed to a vast number of xenobiotics, which are novel chemical structures and to which no defense mechanism has developed during evolution. The discovery of MPTP illustrates that a simple chemical which was used as intermediate in chemical syntheses can turn out to be a major neurotoxin. It is therefore important to study xenobiotics on a large scale for their potential neurotoxicity. We have developed culture systems to study the mechanism of action by which MPTP destroys dopaminergic neurons and to search for neurotoxins which, similar to MPTP, produce toxic effects on dopaminergic neurons. Culture systems offer the advantage that relatively large number of compounds can be tested and that their effects can be assessed in absence of interference by the blood brain barrier or metabolizing enzymes.

Keywords

Tyrosine Hydroxylase Dopaminergic Neuron Dopaminergic Cell Glyoxylic Acid Dopamine Uptake 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. D’Amato R.J., Alexander G.M., Schwartzman R.J., Kitt C.A., Price D.L., Snyder S.H. (1987) Evidence for neuromelanin involvement in MPTP induced neurotoxicity. Nature 327, 324–326.PubMedCrossRefGoogle Scholar
  2. DeLaTorre J.C. (1980) An improved approach to histofluorescence using the SPG method for tissue monoamines. J. Neurosci. Methds. 3,1–5CrossRefGoogle Scholar
  3. Finnegan K.T., Irwin I., Delanney L.E., Ricaurte G.A., Langston J.W. (1987) l,2,3,6-Tetrahydro-1-methyl-4-(methylpyrrol-2-yl) pyridine: studies on the mechanism of action of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine. J. Pharmacol. Exp. Ther. 242. 1144–1151.PubMedGoogle Scholar
  4. Fuller R.W., Robertson, D.W., Hemrick-Luecke S.K. (1986) Comparison of the effects of two 1-methyl-l,2,3,6-tetrahydropyridine analogs, 1-methyl-4-(2-thienyl)-l,2,3,6-tetrahydropyridine and 1-methyl-4-(3-thienyl)-1,2,3,6-tetrahydropyridine, on monoamine oxidase in vitro and on dopamine in mouse brain. J. Pharmacol. Exp. Ther. 240. 415–420.Google Scholar
  5. Fuller R.W., Hemrick-Luecke S.K., Robertson D.W. (1985) Comparison of 1-methyl-4-(p-chlorophenyl)-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and p-chloramphetamine as monoamine depletors. Res. Commun. Chem. Pathol. Pharmacol. 50, 57–65.PubMedGoogle Scholar
  6. Harik S.I., Schmidley J.W., Iacofano L.A., Blue P., Aiora P.K., and Sayre L.M. (1987) On the mechanisms underlying 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity: the effect of perinigral infusion of MPTP, its metabolite and their analogs in the rat. J. Pharmacol. Exp. Ther. 241, 669–676PubMedGoogle Scholar
  7. Heikkila R.E., Hess A., and Duvoisin R.C. (1984a) Dopaminergic neurotoxicity of MPTP in mice. Science 224, 1451–53PubMedCrossRefGoogle Scholar
  8. Heikkila R.E., Manzino L., Cabbat F.S., Duvoisin R.C. (1984b) Protection against the dopaminergic neurotoxicity of MPTP by monoamine oxidase inhibitors. Nature 311, 67–79CrossRefGoogle Scholar
  9. Heikkila R.E., Manzino L., Cabbat F.S., Duvoisin R.C. (1985a) Studies in the oxidation of the dopamine neurotoxin MPTP by monoamine oxidase B.J. Neurochem. 45: 1049–54PubMedCrossRefGoogle Scholar
  10. Heikkila R.E., Manzino L., Cabbat F.S., Duvoisin R.C. (1985b) Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and several of its analogues on the dopaminergic nigrostriatal pathway in mice. Neurosci. Lett. 58, 133–137PubMedCrossRefGoogle Scholar
  11. Hirata Y., Sugimura H., Takei H., and Nagatsu T. (1986) The effects of pyridinium salts, structurally related compound of MPP+, on tyrosine hydroxylation in rat striatal tissue slices. Brain Res. 397, 341–844PubMedCrossRefGoogle Scholar
  12. Javitch J. A. and Snyder S.H. (1984) Uptake of MPP+ by dopaminergic neurons explains selectivity of parkinsonism inducing neurotoxin MPTP. Europ. J. Pharmacol. 106, 455–56CrossRefGoogle Scholar
  13. Johannessen J.N., Chiueh C.C., Burns R.S., and Markey S.P. (1985) Differences in metabolism of MPTP in rodent and primate brain parallel differences in sensitivity to its neurotoxic effects. Life Sci. 36, 219–224PubMedCrossRefGoogle Scholar
  14. Johnson E.M., Manning P.T. (1984) Guanethidine-induced destruction of sympathetic neurons. Int. Rev. Neurobiol., 25, 1–37.PubMedCrossRefGoogle Scholar
  15. Kalaria R.N., Mitchell M.J., and Harik S.l. (1987) MPTP neurotoxicity: correlation with blood-brain-barrier monoamine oxidase activity. Proc. Natl. Acad. Sci. U.S.A. 84, 3521–5PubMedCrossRefGoogle Scholar
  16. Kindt M.V., Heikkila R.E., Nicklas W.J. (1987) Mitochondrial and metabolic toxicity 1-methyl-4-(2’-methyl-phenyl)-1,2,3,6-tetrahydropyridine. J. Pharmacol. Exp. Ther. 242, 858–863.PubMedGoogle Scholar
  17. Langston J.W., Ballard P., Tetrud J.W., and Irwin I.J. (1983) Chronic parkinsonism due to a product of a meperidine analog synthesis. Science, 219:979–980PubMedCrossRefGoogle Scholar
  18. Langston J. W., Irwin I., and Langston E.B. (1984a) Pargyline prevents MPTP induced parkinsonism in primates. Science 225, 1480–82PubMedCrossRefGoogle Scholar
  19. Langston J.W., Irwin I., Langston E.B. and Forno L.S. (1984b) The importance of the ’4–5’ double bond for neurotoxicity in primates of the pyridine derivative MPTP. Neurosci. Lett. 50, 289–294PubMedCrossRefGoogle Scholar
  20. Langston J.E., Irwin, I., and Langston E.B. (1984) Pargyline prevents MPTP-induced parkinsonism in primates. Science 225, 1480.PubMedCrossRefGoogle Scholar
  21. Markey S.P, Johannessen J.N., Chiueh C.C., Burns, R.S. and Herkenham M.A. (1984) Intraneuronal accumulation of a pyridinium metabolite may produce MPTP-induced parkinsonian syndrome in monkey. Nature 311 464–46PubMedCrossRefGoogle Scholar
  22. Mytileneou C., and Cohen G. (1984) MPTP destroys DA neurons in explants of rat embryo mesencephalon. Science 225, 529–531CrossRefGoogle Scholar
  23. Mytileneou C., and Cohen G. (1985) Deprenyl protects dopamine neurons from the neurotoxic effect of 1–4-phenylpyridinium ion. J. Neurochem 45, 1951–53CrossRefGoogle Scholar
  24. Perry T.L., Yong V.W., Wall R.A., Jones K. (1986) Paraquat and two endogenous analogs of the neurotoxic substance N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine do not damage dopaminergic nigrostriatal neurons in the mouse. Neurosci. Lett. 69, 285–289.PubMedCrossRefGoogle Scholar
  25. Pileblad E., and Carlsson A. (1985) Catecholamine-uptake inhibitors prevent the neurotoxicity of MPTP in mouse brain. Neuropharmacol 24, 689–92CrossRefGoogle Scholar
  26. Pressman, B.C. (1963) The effects of alkylguanidines on the energy transfer reactions of mitochondria. J. Biol. Chem. 238, 401–409.Google Scholar
  27. Sanchez-Ramos J.R., Barrett J.N., Goldstein M., Weiner W.J., and Hefti F. (1986) MPP+, but not MPTP is toxic to dopamine neurons in cultures of dissociated rat mesencephalic neurons. Neurosci. Lett. 72, 215–220.PubMedCrossRefGoogle Scholar
  28. Sanchez Ramos J.R., Michel P., Weiner W.J., and Hefti F. (1988) Selective destruction of cultured dopaminergic neurons from fetal rat mesencephalon by 1-methyl-4-phenylpyridinium (MPP+): cytochemical and morphological evidence. J. Neurochem., 50, 1934–1944.PubMedCrossRefGoogle Scholar
  29. Singer T.P., Castagnoli N., 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.PubMedCrossRefGoogle Scholar
  30. Sonsalla P.K., Youngster S.K., Kindt M.V., Heikkila R.E. (1987) Characteristics of 1-methyl-4-(2’-methyl-phenyl)-1,2,3,6-tetrahydio-pyridine-induced neurotoxicity in the mouse. J. Pharmacol. Exp. Ther. 242,850–857.PubMedGoogle Scholar
  31. Youngster S.K., Sonsalla P.K., Heikkila R.E. (1987) Evaluation of the biological activity of several analogs of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahdyropyridine. J. Neurochem. 48,929–934.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Franz Hefti
    • 1
  • Juan R. Sanchez-Ramos
    • 1
  • Patrick P. Michel
    • 1
  • Simon Efange
    • 1
  • Berton C. Pressman
    • 1
  1. 1.Departments of Neurology, Pharmacology, and RadiologyUniversity of MiamiMiamiUSA

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