Involvement of endogenous N-methyl(R)salsolinol in Parkinson’s disease: induction of apoptosis and protection by (-)deprenyl

  • M. Naoi
  • W. Maruyama
  • T. Takahashi
  • Y. Akao
  • Y. Nakagawa
Conference paper


An endogenous dopamine-derived N-methyl(R)salsolinol has been suggested to be involved in the pathogenesis of Parkinson’s disease. In Parkinson’s disease, the level of N-methyl(R)salsolinol increased in cerebrospinal fluid and the high activity of a synthesizing enzyme, (R)salsolinol Nmethyltransferase, was detected in lymphocytes. This isoquinoline induced apoptotic DNA damage in human dopaminergic neuroblastoma SH-SY5Y cells. Among catechol isoquinolines, only N-methylsalsolinol induced apoptosis in the cells, and the scavengers of hydroxyl radicals and antioxidants suppressed DNA damage, suggesting that reactive oxygen species initiate apoptosis. The isoquinoline activated caspase-3 like proteases and a caspase-3 inhibitor protected the cells from DNA damage. (-)Deprenyl, but neither clorgyline nor pargyline, prevented apoptotic cell death. The mechanism of the protection was due to stabilization of mitochondrial membrane potential reduced by the toxin. In Parkinson’s disease apoptosis may be induced in dopamine neurons by this endogenous neurotoxin, and (-)deprenyl may protect them from apoptotic death process.


Mitochondrial Membrane Potential Multiple System Atrophy Dopamine Neuron Multiple System Atrophy Patient Dopaminergic Neurotoxin 
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, Mizoguchi H, Ohishi N, Yagi K (1998) Growth inhibition by overexpression of human DEAD box protein rck/p54 of a guinea pig cell line. FEBS Lett 429: 279–283PubMedCrossRefGoogle Scholar
  2. Anglade P, Vyas S, Javoy-Agid F, Herrero M.T., Michel P.P., Marquez J, Mouatt Priget A, Ruberg M, Hirsch EC, Agid Y (1997) Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 12: 25–31PubMedGoogle Scholar
  3. Carrillo M-C, Kanai S, Nokubo M, Ivy G.O., Sano Y, Kitani K (1992) (-)Deprenyl increases activities of superoxide dismutase and catalase in striatum but not in hippocampus: the sex and age-related differences in the optimal dose in the rat. Exp Neurol 116:286–294Google Scholar
  4. Cohen G, Spina M.B. (1989) Deprenyl suppressed the oxidant stress associated with increased dopamine turnover. Ann Neurol 26: 689–690PubMedCrossRefGoogle Scholar
  5. Cohen G, Pasik P, Cohen B, Leist A, Mitileneou C, Yahr M.D. (1984) Pargyline and (-)deprenyl prevent the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys. Eur J Pharmacol 106: 209–210PubMedCrossRefGoogle Scholar
  6. Koutsilieri E, Chen T-S, Rausch W-D, Riederer P (1996) Selegiline is neuroprotective in primary brain cultures treated with 1-methyl-4-phenylpyridinium Eur J Pharmacol 306: 181–186PubMedCrossRefGoogle Scholar
  7. Kroemer G, Petit P, Zamzami N, Yayssiere J-L, Mignotte B (1995) The biochemistry of programmed cell death. FASEB J 9: 1277–1287PubMedGoogle Scholar
  8. Maruyama W, Nakahara D, Ota M, Takahashi T, Takahashi A, Nagatsu T, Naoi M (1992) N-Methylation of dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, (R)-salsolinol, in rat brains: in vivo micro dialysis study. J Neurochem 59:395–400PubMedCrossRefGoogle Scholar
  9. Maruyama W, Dostert P, Naoi M (1995) Dopamine-derived 1-methyl-6,7-dihydroxyisoquinolines as hydroxyl radical promoters and scavengers in the rat brain: In vivo and in vitro studies. J Neurochem 62: 2635–2643Google Scholar
  10. Maruyama W, Abe T, Tohgi H, Dostert P, Naoi M (1996) A dopaminergic neurotoxin, (R)-N-methylsalsolinol, increases in parkinsonian cerebrospinal fluid. Ann Neurol 40: 119–122PubMedCrossRefGoogle Scholar
  11. Maruyama W, Naoi M, Kasamatsu T, Hashizume Y, Takahashi T, Kohda K, Dostert P (1997a) An endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol, induces DNA damage in human dopaminergic neuroblastoma SH-SY5Y cells. J Neurochem 69: 322–329PubMedCrossRefGoogle Scholar
  12. Maruyama W, Sobue G, Matsubara K, Dostert P, Naoi M (1997b) A dopaminergic neurotoxin, 1 (R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, N-methyl(R)salsolinol, and its oxidation product, 1,2(N)-dimethyl-6,7-dihydroxyisoquinolinium ion, accumulate in the nigro-striatal system of the human brain. Neurosci Lett 223: 61–64PubMedCrossRefGoogle Scholar
  13. Maruyama W, Strolin Benedetti M, Takahashi T, Naoi M (1997c) A neurotoxin Nmethyl(R)salsolinol induces apoptotic cell death in differentiated human dopaminergic neuroblastoma SH-SY5Y cells. Neurosci Lett 232: 147–150PubMedCrossRefGoogle Scholar
  14. Maruyama W, Takahashi T, Naoi M (1998) (-)-Deprenyl protects human dopaminergic neuroblastoma SH-SY5Y cells from apoptosis induced by peroxynitrite and nitric oxide. J Neurochem 70: 2510–2515PubMedCrossRefGoogle Scholar
  15. Mochizuki H, Nakamura N, Nishi K, Mizuno Y (1994) Apoptosis is induced by 1-methyl-4-phenylpyridinium (MPP+) in ventral mesencephalic-striatal co-culture in rat. Neurosci Lett 170: 191–194PubMedCrossRefGoogle Scholar
  16. Mochizuki H, Goto K, Mori H, Mizuno Y (1996) Histochemical detection of apoptosis in Parkinson’s disease. J Neurol Sci 137: 120–123PubMedCrossRefGoogle Scholar
  17. Mutoh T, Tokuda A, Marini A.M., Fujiki N (1994) 1-Methyl-4-phenylpyridinium kills differentiated PC12 cells with a concomitant change in protein phosphorylation. Brain Res 661: 51–55PubMedCrossRefGoogle Scholar
  18. Naoi M, Maruyama W, Zhang J-H, Takahashi T, Deng Y, Dostert P (1995) Enzymatic oxidation of the dopaminergic neurotoxin, 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, into 1,2(N)-dimethyl-6,7 -dihydrooxyisoquino-linium ion. Life Sci 57: 1061–1066PubMedCrossRefGoogle Scholar
  19. Naoi M, Maruyama W, Dostert P, Hashizume Y, Nakahara D, Takahashi T, Ota M (1996a) Dopamine-derived endogenous 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, N-methyl-(R)salsolinol, induced parkinsonism in rat. Brain Res 709: 285–295PubMedCrossRefGoogle Scholar
  20. Naoi M, Maruyama W, Dostert P, Kohda K, Kaiya T (1996b) A novel enzyme enantioselectively synthesizes (R)salsolinol, a precursor of a dopaminergic neurotoxin, Nmethyl( R)salsolinol. Neurosci Lett 2212: 183–186CrossRefGoogle Scholar
  21. Naoi M, Maruyama W, Matsubara K, Hashizume K (1997) A neutral Nmethyltransferase activity in the striatum determines the level of an endogenous MPP+ -like neurotoxin, 1,2-dimethyl-6,7 -dihydroxyisoquinolinium ion, in the substantia nigra of human brains. Neurosci Lett 235: 81–84PubMedCrossRefGoogle Scholar
  22. Naoi M, Maruyama W, Nakao N, Ibi T, Sahashi K, Strolin Benedetti M (1998) (R)Salsolinol N-methyltransferase activity increases in parkinsonian lymphocytes. Ann Neurol 43: 212–216PubMedCrossRefGoogle Scholar
  23. Nicholson D.W., Ali A, Thornberry N.A., Vaillancourt J.P., Ding C.K., Gallant M, Gareau Y, Griffin P.R., Labelle M, Lazebnik Y.A., Munday N.A., Raju S.M., Smulson ME, Yamin T-T, Yu VL, Miller D.K. (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 375: 37–43CrossRefGoogle Scholar
  24. Parkinson’s Study Group (1989) Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 321: 1369–137Google Scholar
  25. Salo P.T., Tatton W.G. (1992) Deprenyl reduces the death of motoneurons caused by axotomy. J Neurosci Res 31: 394–400PubMedCrossRefGoogle Scholar
  26. Semkova I, Wolz P, Schilling M, Krieglstein J (1996) Selegiline enhances NGF synthesis and protects central nervous system neurons from excitotoxic and ischemic damage. Eur J Pharmacol 315: 19–30PubMedCrossRefGoogle Scholar
  27. Southern E.M. (1975) Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol 98: 503–517PubMedCrossRefGoogle Scholar
  28. Tatton W.G., Greenwood C.E. (1991) Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J Neurosci Res 30: 666–672PubMedCrossRefGoogle Scholar
  29. Tatton W.G., Chalmers-Redman R.M.E. (1996) Modulation of gene expression rather than monoamine oxidase inhibition: (-)-Deprenyl-related compounds in controlling neurodegeneration. Neurology 47 [Suppl 3]: S171–S183PubMedCrossRefGoogle Scholar
  30. Wadia J.S., Chalmers-Redman R.M.E., Ju W.J.H., Carlite G.E., Phillips J.L., Frase A.D., Tatton W.G. (1998) Mitochondrial membrane potential and nuclear changes in apoptosis caused by serum and nerve growth factor withdrawal; Time course and modification by (-)-deprenyl. J Neurosci 18: 932–947PubMedGoogle Scholar
  31. Wu R-M, Chiueh C.C., Pert A, Murphy D.L. (1993) Apparent antioxidant effect of (-)-deprenyl on hydroxyl radical formation and nigral injury elicited by MPP+ in vivo. Eur J Pharmacol 243: 241–247PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2000

Authors and Affiliations

  • M. Naoi
    • 1
  • W. Maruyama
    • 2
  • T. Takahashi
    • 3
  • Y. Akao
    • 4
  • Y. Nakagawa
    • 5
  1. 1.Department of Brain SciencesInstitute of Applied BiochemistryMitake, GifuJapan
  2. 2.Department of Basic Gerontology, National Institute for Longevity SciencesLaboratory of Biochemistry and MetabolismObu, AichiJapan
  3. 3.Department of Food and NutritionAichi-Konan CollegeKonan, AichiJapan
  4. 4.Gifu International Institute of BiotechnologyMitake, GifuJapan
  5. 5.The Second Department of Internal MedicineOsaka Medical CollegeTakatsuki, OsakaJapan

Personalised recommendations