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[microM N-methyl(R)salsolinol, almost all the cells died with apoptosis and necrotic cell death was negligible. N-Methyl(R)salsolinol 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, deltapsi(m), using a fluorescent indicator, JC-1. Red fluorescence of J-aggregates representing hyperpolarized deltapsi(m) was found to decrease significantly within 60 min after incubation with N-methyl(R)salsolinol, but not by the (S)-enantiomer at the same concentration. It suggests that mitochondria may recognize the stereo-chemical structure of N-methyl(R) salsolinol. Aliphatic propargylamines, (R)-N-(2-heptyl)-N-methylpropargylamine and (R)-N-(2-heptyl)propargylamine, were found to prevent deltapsim 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.
Department of Basic Gerontology, National Institute for Longevity Sciences, Obu, Aichi, Japan.
W
W
Maruyama
A A
AA
Boulton
B A
BA
Davis
P
P
Dostert
M
M
Naoi
D000480:Alkynes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D005456:Fluorescent Dyes; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D012490:Salsoline Alkaloids / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D000480:Alkynes; D005456:Fluorescent Dyes; D008996:Monoamine Oxidase Inhibitors; C402679:N-2-heptyl-N-methylpropargylamine; D018696:Neuroprotective Agents; D009498:Neurotoxins; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; C032837:salsoline; D004298:Dopamine