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The Importance of MPP+ Localization for the Manifestation of MPTP-Induced Neurotoxicity

  • Andrew Giovanni
  • Patricia K. Sonsalla
  • Richard E. Heikkila
Part of the Advances in Behavioral Biology book series (ABBI, volume 39)

Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin which is very effective in inducing a lesion of the dopaminergic nigrostriatal pathway in several species, including humans, monkeys and mice (Davis et al., 1979; Burns et al., 1983; Langston et al., 1984.; Heikkila et al., 1984a). MPTP provides a means with which to produce dopaminergic deficits in experimental animals which closely mimic those of human Parkinson’s disease. However, the degree of dopaminergic neurotoxicity induced by a given dose of MPTP can vary greatly in these species. For example, rats and mice exhibit marked differences in sensitivity to MPTP, with the rat being relatively unaffected by a dose of MPTP which would produce an 80–90% loss of dopamine in the neostriata of mice. Additionally, there is a considerable difference in sensitivity to MPTP among several strains of mice (Sonsalla and Heikkila, 1986; Sundstrom et al, 1987), and even within a particular strain, older mice are affected to a greater extent than are younger mice by a given dose of MPTP (Ricaurte et al., 1987). In some cases, as with the strains of mice, the differential sensitivity to MPTP-induced neurotoxicity may be explained by the pharmacokinetics of MPTP. More specifically, the amount of the 1-methyl-4-phenylpyridinium species (MPP+), the neurotoxic oxidation product of MPTP, which is found in the neostriata of a particular strain of mice correlates positively with the degree of dopaminergic neurotoxicity induced by MPTP in that strain, relative to the other strains. These data suggest that the brain level, or perhaps more importantly the neostriatal level, of MPP+ is a determinant of MPTP-induced dopaminergic neurotoxicity. Moreover, MAO-B inhibitors have been shown to block the formation of MPP+ in the brain of MPTP-treated animals and also to protect against MPTP-induced neurotoxicity (Heikkila et al., 1984b). In other studies, dopamine uptake inhibitors have been shown to protect against MPTP-induced neurotoxicity, presumably by preventing MPP+ accumulation by dopaminergic nerve terminals (Javitch et al., 1985; Mayer et al., 1986).

Keywords

Dopamine Uptake MPTP Administration Dopaminergic Neurotoxicity Dopaminergic Deficit Dopaminergic Nigrostriatal Pathway 
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. Burns RS, LeWitt PA, Ebert MH, Pakkenberg H, Kopin IJ (1985) The clinical syndrome of striatal dopamine deficiency. Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine ( MPTP ). N.Enql.J.Med., 312, 1418–1421.CrossRefGoogle Scholar
  2. Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, and Kopin IJ (1979) Chronic parkinsonism secondary to intravenous injection of meperidine analogs. Psychiatry Res., 1, 249–254.PubMedCrossRefGoogle Scholar
  3. Heikkila RE, Hess A, Duvoisin RC (1984a) Dopaminergic neurotoxicity of 1-methyl-4-phenyl-l,2,5,6tetrahydropyridine in mice. Science, 224, 1451–1453.PubMedCrossRefGoogle Scholar
  4. Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC (1984b) Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature, 311, 467–469.PubMedCrossRefGoogle Scholar
  5. Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC (1985) Studies on the oxidation of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine by monoamine oxidase B. J.Neurochem., 45, 1049–1054.PubMedCrossRefGoogle Scholar
  6. Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl1,2,3,6-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.PubMedCrossRefGoogle Scholar
  7. Keller HH, and Da Prada, M (1985) Evidence for the release of 1-methyl-4-phenylpyridinium ( MPP’) from rat striatal neurons in vitro. Eur.J.Pharmacol., 119, 247–250.PubMedCrossRefGoogle Scholar
  8. Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidineanalog synthesis. Science, 219, 979–980.PubMedCrossRefGoogle Scholar
  9. Langston JW, Irwin I, Langston EB, Forno LS (1984) Pargyline prevents MPTP-induced parkinsonism in primates. Science, 225, 1480–1482.PubMedCrossRefGoogle Scholar
  10. Mayer RA, Kindt MV, Heikkila RE (1986) Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-l,2,3,6tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport. J.Neurochem., 47, 1073–1079.PubMedCrossRefGoogle Scholar
  11. Reinhard JF Jr, Daniels AJ, Viveros OH (1988) Potentiation by reserpine and tetrabenazine of brain catecholamine depletions by MPTP (1-methyl-4-phenyl-l,2,3,6tetrahydropyridine) in the mouse; evidence for subcellular sequestration as basis for cellular resistance to the toxicant. Neurosci.Lett., 90, 349–353.PubMedCrossRefGoogle Scholar
  12. Ricaurte GA, Irwin I, Forno LS, DeLanney LE, Langston E, Langston JW (1987) Aging and 1-methyl-4-phenyl-l,2,3,6tetrahydropyridine-induced degeneration of dopaminergic neurons in the substantia nigra. Brain.Res., 403, 43–51.PubMedCrossRefGoogle Scholar
  13. Shinka T, Castagnoli N Jr, Wu EY, Hoag MKP, Trevor AJ (1987) Cation-exchange high-performance liquid chromatography assay for the nigrostriatal toxicant MPTP and its monoamine oxidase B generated metabolites in brain tissues. J. Chromatog., 398, 279–287.CrossRefGoogle Scholar
  14. Sonsalla PK, Heikkila RE (1986) The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice. Eur.J.Pharmacol., 129, 339–345.PubMedCrossRefGoogle Scholar
  15. Sundstrom E, Stromberg I, Tsutsumo T, Olson L, Jonsson G (1987) Studies on the effect of 1-methyl-4-phenyl-l,2,3,6tetrahydropyridine (MPTP) on central catecholamine neurons in the C57B1/b mouse. Comparison with three other strains. Brain Res. 405, 26–38.PubMedCrossRefGoogle Scholar
  16. Youngster SK, Heikkila RE (1988) A biological evaluation of some 2’-substituted analogs of MPTP, in: “Progress in Parkinson Research,” F. Hefti and W.J.Weiner, Eds., Plenum Press, New York.Google Scholar
  17. Youngster SK, Nicklas WJ, Heikkila RE (1989) Structure-activity study of the mechanism of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. II. Evaluation of the biological activity of the pyridinium metabolites formed from the monoamine oxidase-catalyzed oxidation of MPTP analogs. J. Pharmacol. ExDtl. Ther., 249, 829–835.Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Andrew Giovanni
    • 1
    • 2
  • Patricia K. Sonsalla
    • 1
    • 2
  • Richard E. Heikkila
    • 1
    • 2
  1. 1.Department of NeurologyUniversity of MedicinePiscatawayUSA
  2. 2.Dentistry of New JerseyRobert Wood Johnson Medical SchoolPiscatawayUSA

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