Apoptosis in MPP+-Treated Mesencephalic-Striatal Co-Culture and MPTP-Induced Hemiparkinsonian Monkeys

  • Hideki Mochizuki
  • Keigo Goto
  • Hisamasa Imai
  • Yoshikuni Mizuno
Part of the Advances in Behavioral Biology book series (ABBI, volume 47)


Apoptosis is a morphologically distinct process of cell death. Recently, non-physiologic agents, such as radiation, toxic substances and drugs, have been found to induce apoptosis. In this study, we report the presence of apoptotic cell death in cultured mesencephalic neurons treated with MPP+ and in the monkey substantia nigra after putaminal injection of MPTP by the TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method. Apoptosis may be an important mechanism of cell death in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) - induced parkinsonism.


Amyotrophic Lateral Sclerosis Tyrosine Hydroxylase TUNEL Method Ventral Mesencephalon Positive Nuclear Staining 


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  1. 1.
    Bums, R.S., Chiueh, C.C., Markey, S.P., Ebert, M.H., Jacobowitz, D., and Kopin, I.J., Aprimate 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, 1983, Proc. Natl. Acad. Sci. USA., 80: 4546–4550.CrossRefGoogle Scholar
  2. 2.
    Chiba, K., Trevor, A.J. and Castagnoli, N. Jr. 1984 Metabolism of the neurotoxic teritially amine, MPTP, by brain monoamine oxidase. Biochem. Biophys. Res. Commun., 120: 574–578.PubMedCrossRefGoogle Scholar
  3. 3.
    Chiba, K., Trevor, A.J. and Castagnoli, N. Jr., 1985 Active uptake of MPP+, metabolite of MPTP, by brain synaptosomes. Biochem. Biophys. Res. Commun., 129: 1228–1232.CrossRefGoogle Scholar
  4. 4.
    Dipasquale, B., Marini, M., and Youle, R.J., Apoptosis and DNA degradation by 1-methyl-4-phenylpyridinium in neurons, 1991, Biochem. Biophys. Res. Commum., 181: 1442–1448.CrossRefGoogle Scholar
  5. 5.
    Dragunow, M., Faull, L. M., Lawlor, P., Beilharz, E. J., Singleton, K., Walker, E. B. and Mee, E., 1995, In situ evidence for DNA fragmentation in Huntington’s disease striatum and Alzheimer’s disease temporal lobe. Neuro Report 6: 1053–1057.Google Scholar
  6. 6.
    Gavrieli, Y., Sherman, Y., and Ben-Sasson, S.A., 1992, Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation, J. Cell Biol., 119: 493–501.PubMedCrossRefGoogle Scholar
  7. 7.
    Imai, H., Nakamura, T., Endo, K. and Narabayashi, H., 1988, Hemiparkinsonism in monkeys after unilateral caudate neurons infusion of 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP): behavior and histology, Brain. Res. 474: 327–332.PubMedCrossRefGoogle Scholar
  8. 8.
    Langston, J.W., Irwin, I., and Langston, E.B., 1984, 1-methyl-4-phenylpyridinium ion (MPP+): Identification of a metabolite of MPTP, a toxin selective to the substantia nigra, Neurosci. Lett., 48: 87–92.PubMedCrossRefGoogle Scholar
  9. 9.
    Lassmann, H., Bancher, C., Breitschopf, H., Wegiel, J., Bobinski, M., Jellinger, K. and Wisniewski, H.M., 1995, Cell death in Alzheimer’s disease evaluated by DNA fragmentation in situ, Acta. Neuropathol., 89: 35–41PubMedCrossRefGoogle Scholar
  10. 10.
    Mizuno, Y., Sone, N., and Saitoh, T. J., 1987, Effects of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion on activities of the enzymes in the electron transport system in mouse brain, J. Neurochem., 48: 1787–1793.PubMedCrossRefGoogle Scholar
  11. 11.
    Mochizuki, H., Nishi, K., Mizuno, Y., 1993, Iron-melanin complex is toxic to dopaminergic neurons in a nigrostriatal co-culture, Neurodegeneration 2: 1–7Google Scholar
  12. 12.
    Mochizuki, H., Imai, H., Endo, K., Yokomizo, K., Murata, Y., Hattori, N., Mizuno, Y., 1994a, Iron accumulation in the substantia nigral of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced hemiparkinsonian monkeys, Neurosci. Lett. 168: 251–253.PubMedCrossRefGoogle Scholar
  13. 13.
    Mochizuki, H., Nakamura, N., Nishi, K. and Mizuno, Y., 1994b, Apoptosis is induced by 1-methyl-4-phenylpyridinium ion (MPP+) in ventral mesencephalic-striatal co-culture in rat, Neurosci. Lett. 170: 191–194PubMedCrossRefGoogle Scholar
  14. 14.
    Mochizuki, H., Goto, K., Hideo, M. and Mizuno, Y., 1996, Histochemical detection of apoptosis in Parkinson’s disease., J. Neurol. Sci. in pressGoogle Scholar
  15. 15.
    Nishi, K., Mochizuki, H., Furukawa, Y., and Mizuno, Y., 1994, Neurotoxicities of 1-methyl-4-phenylpyridinium ion (MPP+) and tetrahydroisoquinoline derivates on dopaminergic neurons in ventral mesencephalic-striatal co-culture, Neurodegeneration, 3: 33–42.Google Scholar
  16. 16.
    Ratan R. R., Murphy, T. T. and Baraban, J. M., 1994, Oxidative stress induces apoptosis in embryonic cortical neurons, J. Neurochem. 62: 376–379.PubMedCrossRefGoogle Scholar
  17. 17.
    Su, J. H., Anderson, A. J., Cummings, B. J. and Cotman, C. W., 1994, Immunohistochemical evidence for apoptosis in Alzheimer’s disease, NeuroReport, 5: 2529–33PubMedCrossRefGoogle Scholar
  18. 18.
    Tatton, W. G., Ju, W.Y.L., Holland, D.P., Tai, C. and Kwan, M., 1994, (-)-Deprenyl reduces PC12 cell apoptosis by inducing new protein synthesis, J. Neurochem., 63: 1572–1575.PubMedCrossRefGoogle Scholar
  19. 19.
    Wyllie, A.H., Kerr, J.F.F.R. and Currie, A.R., 1980, Cell death: the significance of apoptosis, Int. Rev. Cytol. 68:251–306.PubMedCrossRefGoogle Scholar
  20. 20.
    Wolvetang EJ, Johnson KL, Krauer K, et al., 1994, Mitochondrial respiratory chain inhibitors induce apoptosis, Febs Lett 339:40–44PubMedCrossRefGoogle Scholar
  21. 21.
    Yoshiyama, Y., Yamada, T., Asanuma, K. and Asahi, T., 1994, Apoptosis related antigen, Le(Y) and nick-end labeling are positive in spinal motor neurons in amyotrophic lateral sclerosis, Acta. Neuropathol. Beri, 88:207–211CrossRefGoogle Scholar
  22. 22.
    Ziv, I., Melamed, E., Nardi, N., Luria, D., Achiron, A., Offen, D. and Barzilai, A., 1994, Dopamine induces apoptosis-like cell death in cultured chick sympathetic neurons-a possible novel pathogetic mechanism in Parkinson’s disease, Neurosci. Lett., 170:136–140PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Hideki Mochizuki
    • 1
  • Keigo Goto
    • 1
  • Hisamasa Imai
    • 1
  • Yoshikuni Mizuno
    • 1
  1. 1.Department of NeurologyJuntendo University School of MedicineBunkyo-ku, Tokyo 113Japan

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