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COX-2 regulates the insulin-like growth factor I-induced potentiation of Zn2+-toxicity in primary cortical culture
- COX-2 regulates the insulin-like growth factor I-induced potentiation of Zn2+-toxicity in primary cortical culture
- Im J.-Y.; Kim D.; Lee K.-W.; Kim J.-B.; Lee J.-K.; Dong S.K.; Young I.L.; Ha K.-S.; Joe C.O.; Han P.-L.
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- Molecular Pharmacology
- Molecular Pharmacology vol. 66, no. 3, pp. 368 - 376
- SCI; SCIE; SCOPUS
- Document Type
- 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.
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