Phosphatidylinositol 3-kinase-mediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I.
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.
Ryu
B R
BR
Department of Pharmacology, Ajou University School of Medicine, Suwon, Kyungkido, Korea.
Ko
H W
HW
Jou
I
I
Noh
J S
JS
Gwag
B J
BJ
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007501:Iron / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009336:Necrosis; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D019311:Staurosporine / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D005419:Flavonoids; D007004:Hypoglycemic Agents; D007328:Insulin; D007329:Insulin Antagonists; D009025:Morpholines; D018696:Neuroprotective Agents; D010761:Phosphorus Radioisotopes; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019328:Buthionine Sulfoximine; D016202:N-Methylaspartate; D007334:Insulin-Like Growth Factor I; D000255:Adenosine Triphosphate; D007501:Iron; D019869:Phosphatidylinositol 3-Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019311:Staurosporine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin