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.