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 N-methyltransferase, 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.
Naoi
M
M
Department of Brain Sciences, Institute of Applied Biochemistry, Mitake, Gifu, Japan. mnaoi@quartz.ocn.ne.jp
Maruyama
W
W
Takahashi
T
T
Akao
Y
Y
Nakagawa
Y
Y
D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010300:Parkinson Disease / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D012490:Salsoline Alkaloids / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000494:pharmacology; D012642:Selegiline / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D018696:Neuroprotective Agents; D009842:Oligopeptides; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D012642:Selegiline; C032837:salsoline; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D004298:Dopamine