COX-2 regulates the insulin-like growth factor I-induced potentiation of Zn2+-toxicity in primary cortical culture

Joo Young Im, Doyeun Kim, Kang Woo Lee, Jung Bin Kim, Ja Kyeong Lee, Sik Kim Dong, Ik Lee Young, Kwon Soo Ha, Cheol O. Joe, Pyung Lim Han

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


The pretreatment of cultured cortical neurons with neurotrophic factors markedly potentiates the cytotoxicity induced by low concentrations of Zn 2+ or excitotoxins. In the current study, we investigated the mechanism underlying the insulin-like growth factor-I (IGF-I)-induced Zn 2+ 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-enhanced cell death was blocked by the COX-2-specific inhibitors N-[2-(cyclohexyloxyl)-4- nitrophenyl]-methane sulfonamide (NS-398; 10-100 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'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-induced potentiation of Zn2+ toxicity and that enhanced COX-2 activity leads to a decrease in the cell's reducing power and an increase in ROS accumulation in primary cortical cultures.

Original languageEnglish
Pages (from-to)368-376
Number of pages9
JournalMolecular Pharmacology
Issue number3
StatePublished - Sep 2004


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