Anti-apoptotic and pro-apoptotic effect of NEPP11 on manganese-induced apoptosis and JNK pathway activation in PC12 cells.
Neurite outgrowth-promoting prostaglandins (NEPPs), cyclopentenone prostaglandin derivatives, are found to be neurotrophic. These small organic compounds promote neurite outgrowth of PC12 cells and dorsal root ganglion explants in the presence of nerve growth factor, and prevent neuronal cell death of HT22 cells and cortical neurons induced by various stimuli. In this study, we examined whether NEPP11 prevents manganese-induced apoptosis of PC12 cells. NEPP11 (5 microM) attenuated manganese-induced DNA fragmentation by approximately 50%. In addition, NEPP11 partially prevented manganese-induced c-Jun phosphorylation and c-Jun N-terminal kinase (JNK) phosphorylation determined by Western blotting. Inhibition of the JNK signaling pathway by NEPP11 appeared to be selective, because NEPP11 did not inhibit manganese-induced activation of p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase1/2 (ERK1/2), MEK1/2 and p70 S6 kinase (p70S6K) in PC12 cells. In contrast, NEPP11 alone was toxic at higher concentrations (>10 microM) producing DNA fragmentation and activation of the JNK pathway. Molecular modifications of NEPP11 may strengthen its inhibitory effects on the JNK pathway while preventing its cytotoxicity, and thus may become a useful small molecule reagent for the treatment of manganese toxicity and other similar neurodegenerative processes.
Hirata
Yoko
Y
Department of Biomolecular Science, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. yoko@biomol.gifu-u.ac.jp
Furuta
Kyoji
K
Miyazaki
Satoshi
S
Suzuki
Masaaki
M
Kiuchi
Kazutoshi
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D016758:Genes, jun / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D048670:MAP Kinase Kinase 4; D008345:Manganese / Q000494:pharmacology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D015230:Prostaglandin D2 / Q000031:analogs & derivatives; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
C424427:NEPP11 compound; D011453:Prostaglandins; D008345:Manganese; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D015230:Prostaglandin D2