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Insulin‐Induced Oxidative Neuronal Injury in Cortical Culture: Mediation by Induced N‐Methyl‐D‐aspartate Receptors
Author(s) -
Noh KyungMin,
Lee JongCheol,
Ahn YoungHo,
Hong Seung Hwan,
Koh JaeYoung
Publication year - 1999
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1080/713803514
Subject(s) - insulin receptor , neurotoxicity , neuroprotection , excitotoxicity , insulin , tyrosine kinase , nmda receptor , kinase , protein kinase c , biology , endocrinology , medicine , chemistry , microbiology and biotechnology , receptor , signal transduction , pharmacology , biochemistry , insulin resistance , toxicity
While effectively attenuating neuronal apoptosis in mouse cortical culture, insulin paradoxically induced neuronal necrosis with 48 h of exposure. The insulin neurotoxicity was blocked by an antioxidant but not by caspase inhibitors. Exposure to insulin led to tyrosine phosphorylation of the insulin receptor and the insulin‐like growth factor‐1 (IGF‐1) receptor and activation of protein kinase C (PKC) and phosphoinositide 3‐kinase (PI3‐kinase). Inhibitors of tyrosine kinase and PKC, but not PI3‐kinase, attenuated the insulin neurotoxicity. Conversely, the inhibitor of PI3‐kinase but not PKC reversed the antiapoptotic effect of insulin. Suggesting that the gene activity‐dependent emergence of excitotoxicity contributed to insulin neurotoxicity, macromolecule synthesis inhibitors and N‐methyl‐D‐aspartate (NMDA) antagonists blocked it. Consistently, exposure to insulin increased the level of the NR2A subunit of the NMDA receptor without much altering NR1 or NR2B levels. The present study suggests that insulin can be both neuroprotective and neurotoxic in the same cell system but by way of different signaling cascades.