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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

COX-2 Regulates the insulin-like growth factor I-induced potentiation of Zn(2+)-toxicity in primary cortical culture.

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 microM Zn(2+) 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 microM) and 1-[(4-methylsulfonyl)phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl]pyrazole (SC58125; 10 microM) and by the antioxidant trolox (30 microM). 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 Zn(2+) 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 Zn(2+) showed consistently enhanced reactive oxygen species production, which was repressed by NS-398 and SC58125. Cortical neurons treated with Zn(2+) 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 Zn(2+) 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.[1]


  1. COX-2 Regulates the insulin-like growth factor I-induced potentiation of Zn(2+)-toxicity in primary cortical culture. Im, J.Y., Kim, D., Lee, K.W., Kim, J.B., Lee, J.K., Kim, D.S., Lee, Y.I., Ha, K.S., Joe, C.O., Han, P.L. Mol. Pharmacol. (2004) [Pubmed]
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