Differential effect of nerve growth factor on dopaminergic neurotoxin-induced apoptosis.
Both rotenone and manganese are possible neurotoxins for a wide variety of cell and neuronal types including dopaminergic neurons and induce apoptosis in various cells. Neurotrophic factors have the potential for therapeutic development when used to prevent Parkinson's disease. In this paper, we focused on the differences between rotenone and manganese as toxins, and characterized the influence of neurotrophic factors on toxin-induced apoptosis in PC12 cells. There were distinct differences in intracellular mechanisms between rotenone- and manganese-induced apoptosis such as the production of reactive oxygen species, the response to antioxidants, and the activation of the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Nerve growth factor (NGF) almost completely prevented rotenone-induced but not manganese-induced caspase activation and DNA fragmentation. The differential effect of NGF was found to be mainly due to the down-regulation of the Trk tyrosine kinase receptor by manganese but not by rotenone. Prevention of rotenone-induced apoptosis by NGF was attenuated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, but not MAPK kinase (MEK) inhibitors, PD98059 or U0126. These results demonstrate that the potential neurotoxins for dopaminergic cells exert their toxic effect by activation of different signaling pathways of apoptosis and that NGF prevents rotenone-induced apoptosis through the activation of the PI 3-kinase pathway not MAPK pathway.
Hirata
Yoko
Y
Department of Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan. yoko@biomol.gifu-u.ac.jp
Meguro
Tomotaka
T
Kiuchi
Kazutoshi
K
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008345:Manganese / Q000037:antagonists & inhibitors / Q000633:toxicity; D020932:Nerve Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D016716:PC12 Cells; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D012402:Rotenone / Q000037:antagonists & inhibitors / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
D000975:Antioxidants; D020169:Caspases; D004298:Dopamine; D004791:Enzyme Inhibitors; D008345:Manganese; D020932:Nerve Growth Factor; D009498:Neurotoxins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D020794:Receptor Protein-Tyrosine Kinases; D012402:Rotenone