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 inje ction in the striatum, was found to induce apoptosis in dopaminergic neurob lastoma SH-SY5Y cells. After 12-h incubation with 500 muM N-methyl(R)salsol inol, almost all the cells died with apoptosis and necrotic cell death was negligible. N-Methyl(R)sasolinol was much more potent to induce apoptosis t han the (S)-enantiomer. The mechanism of apoptosis was studied in relation to changes in mitochondrial membrane potential, Delta Psim, using a fluores cent indicator, JC-1. Red fluorescence of J-aggregates representing hyperpo larized Delta Psim was found to decrease significantly within 60min after i ncubation 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 r ole in the induction of apoptosis by the neurotoxin and the prevention by a liphatic propargylamines.