@article {Im368, author = {Joo-Young Im and Doyeun Kim and Kang-Woo Lee and Jung-Bin Kim and Ja-Kyeong Lee and Dong Sik Kim and Young Ik Lee and Kwon-Soo Ha and Cheol O Joe and Pyung-Lim Han}, title = {COX-2 Regulates the Insulin-Like Growth Factor I{\textendash}Induced Potentiation of Zn2+-Toxicity in Primary Cortical Culture}, volume = {66}, number = {3}, pages = {368--376}, year = {2004}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The pretreatment of cultured cortical neurons with neurotrophic factors markedly potentiates the cytotoxicity induced by low concentrations of Zn2+ or excitotoxins. In the current study, we investigated the mechanism underlying the insulin-like growth factor-I (IGF-I)-induced Zn2+ toxicity potentiation. The pretreatment of primary cortical cultures for more than 12 h with 100 ng/ml of IGF-I increased the cytotoxicity induced by 80 μM Zn2+ by more than 2-fold. The IGF-I{\textendash}enhanced cell death was blocked by the COX-2{\textendash}specific inhibitors N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398; 10{\textendash}100 μM) and 1-[(4-methylsulfonyl)phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl]pyrazole (SC58125; 10 μM) and by the antioxidant trolox (30 μM). In addition, it was observed that COX-2 expression was increased 12 to 24 h after IGF-I treatment. Preincubation of cortical cultures with IGF-I increased arachidonic acid (AA)-induced cytotoxicity, and AA increased Zn2+ toxicity, which suggested the involvement of COX activity in these cellular responses. Moreover, enhanced COX-2 activity led to a decrease in the cell{\textquoteright}s reducing power, as indicated by a gradual depletion of intracellular GSH. Cortical neurons pretreated with IGF-I and then Zn2+ showed consistently enhanced reactive oxygen species production, which was repressed by NS-398 and SC58125. Cortical neurons treated with Zn2+ and then AA displayed the increased ROS production, which was also suppressed by NS-398 and SC58125. These results suggest that COX-2 is an endogenous factor responsible for the IGF-I{\textendash}induced potentiation of Zn2+ toxicity and that enhanced COX-2 activity leads to a decrease in the cell{\textquoteright}s reducing power and an increase in ROS accumulation in primary cortical cultures.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/66/3/368}, eprint = {https://molpharm.aspetjournals.org/content/66/3/368.full.pdf}, journal = {Molecular Pharmacology} }