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Molecular Pharmacology

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Research ArticleArticle

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, Dong Sik Kim, Young Ik Lee, Kwon-Soo Ha, Cheol O Joe and Pyung-Lim Han
Molecular Pharmacology September 2004, 66 (3) 368-376;
Joo-Young Im
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Doyeun Kim
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Kang-Woo Lee
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Jung-Bin Kim
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Ja-Kyeong Lee
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Dong Sik Kim
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Young Ik Lee
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Kwon-Soo Ha
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Cheol O Joe
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Pyung-Lim Han
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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–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.

  • Received December 15, 2003.
  • Accepted May 13, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 66 (3)
Molecular Pharmacology
Vol. 66, Issue 3
1 Sep 2004
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Research ArticleArticle

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, Dong Sik Kim, Young Ik Lee, Kwon-Soo Ha, Cheol O Joe and Pyung-Lim Han
Molecular Pharmacology September 1, 2004, 66 (3) 368-376;

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Research ArticleArticle

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, Dong Sik Kim, Young Ik Lee, Kwon-Soo Ha, Cheol O Joe and Pyung-Lim Han
Molecular Pharmacology September 1, 2004, 66 (3) 368-376;
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