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

Endogenous N-methyl(R)salsolinol, which caused parkinsonism in rats by injection in the striatum, was found to induce apoptosis in dopaminergic neuroblastoma SH-SY5Y cells. After 12-h incubation with 500 muM N-methyl(R)salsolinol, almost all the cells died with apoptosis and necrotic cell death was negligible. N-Methyl(R)sasolinol was much more potent to induce apoptosis than the (S)-enantiomer. The mechanism of apoptosis was studied in relation to changes in mitochondrial membrane potential, Delta Psim, using a fluorescent indicator, JC-1. Red fluorescence of J-aggregates representing hyperpolarized Delta Psim was found to decrease significantly within 60min after incubation with N-methyl(li)salsolinol, but not by the (S)-enantiomer at the same concentration. It suggests that mitochondria may recognize the stereo-chemical structure of N-melhyl(R) salsolinol. Aliphatic propargylamines, (R)-N-(2-heptyl) -N-methylpropargylamine and (R)-N-(2-heptyl)propargylamine, were found to prevent Delta Psim loss and subsequent apoptosis induced by N-methyl(R)salsolinol. These results suggest that mitochondria play a key role in the induction of apoptosis by the neurotoxin and the prevention by aliphatic propargylamines.