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

Title
COX-2 regulates the insulin-like growth factor I-induced potentiation of Zn2+-toxicity in primary cortical culture
Authors
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
한평림
SCOPUS Author ID
한평림scopus
Issue Date
2004
Journal Title
Molecular Pharmacology
ISSN
0026-895XJCR Link
Citation
Molecular Pharmacology vol. 66, no. 3, pp. 368 - 376
Indexed
SCI; SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
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.
DOI
10.1124/mol.66.3.
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일반대학원 > 뇌·인지과학과 > Journal papers
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