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Phosphatidylinositol 3-kinase-mediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I.

Authors
Ryu, BR; Ko, HW; Jou, I; Noh, JS; Gwag, BJ
Citation
Journal of neurobiology, 39(4):536-546, 1999
Journal Title
Journal of neurobiology
ISSN
0022-30341097-4695
Abstract
We examined effects of two insulin-like growth factors, insulin and insulin-like growth factor-I (IGF-I), against apoptosis, excitotoxicity, and free radical neurotoxicity in cortical cell cultures. Like IGF-I, insulin attenuated serum deprivation-induced neuronal apoptosis in a dose-dependent manner at 10-100 ng/mL. The anti-apoptosis effect of insulin against serum deprivation disappeared by addition of a broad protein kinase inhibitor, staurosporine, but not by calphostin C, a selective protein kinase C inhibitor. Addition of PD98059, a mitogen-activated protein kinase kinase (MAPKK) inhibitor, blocked insulin-induced activation of extracellular signal-regulated protein kinases (ERK1/2) without altering the neuroprotective effect of insulin. Cortical neurons underwent activation of phosphatidylinositol (PI) 3-kinase as early as 1 min after exposure to insulin. Inclusion of wortmannin or LY294002, selective inhibitors of PI 3-K, reversed the insulin effect against apoptosis. In contrast to the anti-apoptosis effect, neither insulin nor IGF-I protected excitotoxic neuronal necrosis following continuous exposure to 15 microM N-methyl-D-aspartate or 40 microM kainate for 24 h. Surprisingly, concurrent inclusion of 50 ng/mL insulin or IGF-I aggravated free radical-induced neuronal necrosis over 24 h following continuous exposure to 10 microM Fe2+ or 100 microM buthionine sulfoximine. Wortmannin or LY294002 also reversed this potentiation effect of insulin. These results suggest that insulin-like growth factors act as anti-apoptosis factor and pro-oxidant depending upon the activation of PI 3-kinase.
MeSH terms
Adenosine Triphosphate/pharmacologyAndrostadienes/pharmacologyAnimalsApoptosis/drug effectsApoptosis/physiology*Buthionine Sulfoximine/pharmacologyCalcium-Calmodulin-Dependent Protein Kinases/metabolismCells, CulturedChromones/pharmacologyEnzyme Activation/drug effectsEnzyme Activation/physiologyEnzyme Inhibitors/pharmacologyExcitatory Amino Acid Agonists/pharmacologyFlavonoids/pharmacologyHypoglycemic Agents/pharmacology*Insulin/pharmacology*Insulin Antagonists/pharmacologyInsulin-Like Growth Factor I/pharmacology*Iron/pharmacologyMiceMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein Kinases*Morpholines/pharmacologyN-Methylaspartate/pharmacologyNecrosisNeocortex/cytologyNeurons/cytology*Neurons/drug effectsNeurons/enzymologyNeuroprotective Agents/pharmacologyOxidative Stress/physiologyPhosphatidylinositol 3-Kinases/metabolism*Phosphorus Radioisotopes/diagnostic usePhosphorylationStaurosporine/pharmacology
DOI
10.1002/(SICI)1097-4695(19990615)39:4%3C536::AID-NEU7%3E3.0.CO;2-J
PMID
10380075
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Psychiatry & Behavioural Sciences
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
주, 일로노, 재성곽, 병주
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