Mitochondria determine the survival and death in apoptosis by an endogenous neurotoxin, N-methyl(R)salsolinol, and neuroprotection by propargylamines.
In neurodegenerative disorders, such as Parkinson's disease, selective neuronal death characterizes clinical signs and symptoms. Recently apoptosis was reported to be a common type of cell death in some disorders, and well-controlled apoptotic cascade is proposed to be a target of neuroprotective therapy. In our studies to find endogenous neurotoxins as a pathogenic factor in Parkinson's disease, dopamine-derived N-methyl(R)salsolinol was found to induce apoptosis in dopamine neurons of rat models of Parkinson's disease. In human dopaminergic SH-SY5Y cells, apoptosis was initiated by decline in mitochondrial membrane potential, and anti-apoptotic Bcl-2 family protein regulated apoptotic signal transduction. In addition, a series of propargylamines were found to prevent apoptosis through stabilization of mitochondrial membrane potential, which also involved Bcl-2. The role of mitochondria and the involvement of Bcl-2 in apoptosis and neuroprotection were clearly demonstrated using isolated mitochondria. These results indicate that mitochondria are the site to determine the cell death induced by neurotoxins and also the neuroprotection by anti-apoptotic propargylamines.
Department of Brain Sciences, Institute of Applied Biochemistry, Mitake, Gifu, Japan. mnaoi@giib.or.jp
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Naoi
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Maruyama
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Akao
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Yi
D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology*; D008930:Mitochondria, Liver / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012490:Salsoline Alkaloids / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000502:physiology
D000480:Alkynes; D007189:Indans; C402679:N-2-heptyl-N-methylpropargylamine; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012490:Salsoline Alkaloids; D044005:Tetrahydroisoquinolines; C031967:rasagiline; C032837:salsoline