Involvement of endogenous N-methyl(R)salsolinol in Parkinson’s disease: induction of apoptosis and protection by (-)deprenyl
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.
KeywordsMitochondrial Membrane Potential Multiple System Atrophy Dopamine Neuron Multiple System Atrophy Patient Dopaminergic Neurotoxin
Unable to display preview. Download preview PDF.
- 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
- 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
- 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
- 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
- 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
- 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
- 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