Models of Parkinson’s Disease

  • Makoto Naoi
  • Wakako Maruyama
Part of the Advances in Behavioral Biology book series (ABBI, volume 53)


Parkinson’s disease (PD) at cellular level is characterized by selective death of dopamine neurons in nigral pars compacta. The type of cell death remains an enigma, even though recent results suggest that apoptosis may be a common type of cell death. Since the discovery of a neurotoxin selective to dopamine neurons, l-methyl-4-phenyl-1, 2, 3, 6-tetrahydro-pyridine (MPTP), various types of animal and cell models have been proposed to clarify the pathogenesis of PD. In this paper, an endogenous dopaminergic neurotoxin, N-methyl-(R)salsolinol [NM(R)Sal] was used to prepare the animal and cell models, and the mechanism underlying the selective degeneration of dopamine neurons was studied. By use of the cell model, a series of (-)deprenyl (selegiline) related propargylamines showed neuroprotective functions against apoptosis induced by the neurotoxin. These results are discussed in relation to the validity of animal and cell models in the study of PD and related neurodegenerative disorders.


Cell Model Dopamine Neuron Selective Degeneration Parkinsonian Brain Selective Death 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akao, Y., Nakagawa, Y., Maruyama, W., Takahashi, T., and Naoi, M., 1999, Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, is mediated by activation of caspase 3. Neurosci. Lett., 267: 153–156.PubMedCrossRefGoogle Scholar
  2. Hartmann, A., Hunot, S., Michel, P. P., Muriel, M.-P., Vyas, S., Faucheux, B. A., Mouatt-Prigent, A., Turmel, H., Srinivasan, A., Ruberg, M., Evan, G. I., Agis, V., and Hirsch, E. C., 2000, Caspase 3: A vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc. Natl. Acad. Sci. USA, 97: 2875–2880.PubMedCrossRefGoogle Scholar
  3. Maruyama, W., Abe, T., Tohgi, H., Dostert, P., and Naoi, M., 1996, A dopaminergic neurotoxin, (R)-N-methylsalsolinol, increases in parkinsonian cerebrospinal fluid. Ann. Neurol. 40:119–122.PubMedCrossRefGoogle Scholar
  4. Maruyama, W., Akao, Y., Youdim, M. B. H., and Naoi, M., 2000, Neurotoxins induce apoptosis in dopamine neurons: protection by N-propargylamine-l(R)- and (S)-aminoindan, rasagiline and TV 1022. J. Neural Transm. [Suppl] 60: 171–186.Google Scholar
  5. Maruyama, W., Boulton, A. A., Davis B. A., Dostert, P., and Naoi, M., 2001a, Enantio-specific induction of apoptosis by an endogenous neurotoxin, N-methyl(R)salsolinol, in dopaminergic SH-SY5Y cells: suppression of apoptosis by N-(2-heptyl)-N-methylpropargylamine. J. Neural Transm. 108: 11–24.PubMedCrossRefGoogle Scholar
  6. Maruyama, W., Akao, Y., Youdim, M. B. H., Davis, B. A., and Naoi, M. 2001b, Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehydes-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J. Neurochem. In press.Google Scholar
  7. Maruyama, W., Youdim, M. B. H., Naoi, M., 2001c, Anti-apoptotic properties of rasagiline, JV-propargylamine- l(R)-aminoindan, and its optical (5)-isomer, TV 1022. Ann. N. Y Acad. Sci. 939: 320–329.PubMedCrossRefGoogle Scholar
  8. Nagatsu, T., Mogi, M., Ichinose, H., and Togari, A., 2000, Changes in cytokines and neurotrophins in Parkinson’s disease. J. Neural Transm. [Suppl] 60: 277–290.Google Scholar
  9. Naoi, M., Maruyama, W., Dostert, P., Hashizume, Y, Nakahara, D., Takahashi, T, and Ota, M., 1996a, Dopamine-derived endogenous l(R), 2(7v0-dimethyl-6, 7-dihydroxy-l, 2, 3, 4-tetrahydroisoquinoline, N-methyl(R)salsolinol, induced parkinsonism in rat: biochemical, pathological and behavioral studies. Brain Res. 709: 285–295.PubMedCrossRefGoogle Scholar
  10. Naoi, M., Maruyama, W., Dostert, P., Kodak, K., and Kaiya, T., 1996b, A novel enzyme enantio-selectively synthesizes (R)salsolinol, a precursor of a dopaminergic neurotoxin, N-methyl(R)salsolinol. Neurosci. Lett. 212. 183–186.PubMedCrossRefGoogle Scholar
  11. Naoi, M., Maruyama, W., Matsubara, K., and Hashizume Y., 1997, A neutral N-methyltransferase activity in the striatum determines the level of an endogenous MPP+-like neurotoxin, l, 2-dimethyl-6, 7-dihydroxyisoquinolinium ion, in the substantia nigra of human brains. Neurosci. Lett 235: 81–84PubMedCrossRefGoogle Scholar
  12. Naoi, M., Maruyama, W., Nakao, N., Ibi, T., Sahashi, K., and Strolin Benedetti, M., 1998, (R)Salsolinol N-methyltransferase activity increases in parkinsonian lymphocytes. Ann. Neurol.43: 212–216.PubMedCrossRefGoogle Scholar
  13. Naoi, M. and Maruyama, W., 1999, N-Methyl(R)salsolinol, a dopamine neurotoxin, in Parkinson’s disease. Adv. Neurol. 80: 259–264.PubMedGoogle Scholar
  14. Naoi, M., Maruyama, W, Akao, Y., Zhang, J., and Parvez, H., 2000, Apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, in dopamine neurons. Toxicology 153:123–141.PubMedCrossRefGoogle Scholar
  15. Parkinson’s Study Group, 1993, Effect of deprenyl on the progression of disability in early Parkinson’s disease. N. Eng. J. Med. 42: 176–183.Google Scholar
  16. Tsujimoto, Y. and Shimizu, S., 2000, Bcl-2 family: Life-or-death switch. FEBS Lett. 466: 6–10PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Makoto Naoi
    • 1
  • Wakako Maruyama
    • 2
  1. 1.Department of Brain SciencesInstitute of Applied BiochemistryGifuJapan
  2. 2.Department of Basic GerontologyNational Institute for Longevity SciencesAichiJapan

Personalised recommendations