| Summary: | 碩士 === 台北醫學院 === 生物醫學技術研究所 === 89 === Inducible nitric oxide synthase (iNOS) activity plays important roles in Alzheimer’s disease and other neurodegeneration diseases. The mitogen-activated protein kinase (MAPK) pathway is believed to function as an important mediator of iNOS expression. In the present study, we investigated the role of the p38 MAPK signaling pathway in advanced glycosylation end products (AGEs)-induced iNOS expression in C6 glioma cells. AGEs caused a dose-dependent increase of nitrite accumulation in C6 glioma cells. The AGEs-stimulated nitrite production from C6 glioma cells was inhibited by actinomycin D, cycloheximide, and the NO synthase inhibitor, Nw-nitro-L-arginine methyl ester (l-NAME), suggesting that the increase of AGEs-induced nitrite release is due to iNOS up-regulation. Consistently, treatment of C6 glioma cells with AGEs induced iNOS protein expression. The tyrosine kinase inhibitor (genistein & tyrphostin), the Ras-farnesyl transferase inhibitor (FPT inhibitor-II), the p38 MAPK inhibitor (SB203580), or the MEK inhibitor (PD98059) suppressed AGEs-induced iNOS expression and nitrite release from C6 glioma cells. AGEs activated p38 MAPK in C6 glioma cells, and this effect was blocked by genisteine (20 mM), tyrphostin (30 mM), FPT inhibitor-II (20 mM), and SB203580 (10 mM). AGEs also activated ERK in C6 glioma cells, and this effect was blocked by genisteine (30 mM), FPT inhibitor-II (30 mM), and PD98059 (10 mM). Taken together, our data suggest that AGEs may activate the pathways of tyrosine kinase and Ras to induce p38 MAPK and ERK activation, which in turn induces iNOS expression and NO production in C6 glioma cells.
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