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

Bo Rum Ryu, Hyuk Wan Ko, Ilo Jou, Jai Sung Noh, Byoung Joo Gwag

Research output: Contribution to journalArticle

90 Citations (Scopus)

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 μM N-methyl-D-aspartate or 40 μM 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 μM Fe2+ or 100 μM 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 uon the activation of PI 3- kinase.

Original languageEnglish
Pages (from-to)536-546
Number of pages11
JournalJournal of Neurobiology
Volume39
Issue number4
DOIs
Publication statusPublished - 1999 Jun 15

Fingerprint

Phosphatidylinositol 3-Kinase
Insulin-Like Growth Factor I
Necrosis
Insulin
Apoptosis
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Somatomedins
Protein Kinase Inhibitors
Free Radicals
Buthionine Sulfoximine
Staurosporine
Protein C Inhibitor
Kainic Acid
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Neuroprotective Agents
N-Methylaspartate
Phosphatidylinositols
Serum
Protein Kinases

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Cellular and Molecular Neuroscience

Cite this

Ryu, Bo Rum ; Ko, Hyuk Wan ; Jou, Ilo ; Noh, Jai Sung ; Gwag, Byoung Joo. / Phosphatidylinositol 3-kinase-mediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I. In: Journal of Neurobiology. 1999 ; Vol. 39, No. 4. pp. 536-546.
@article{853cc8441f1f4bc4851e62b843cd001c,
title = "Phosphatidylinositol 3-kinase-mediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I",
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 μM N-methyl-D-aspartate or 40 μM 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 μM Fe2+ or 100 μM 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 uon the activation of PI 3- kinase.",
author = "Ryu, {Bo Rum} and Ko, {Hyuk Wan} and Ilo Jou and Noh, {Jai Sung} and Gwag, {Byoung Joo}",
year = "1999",
month = "6",
day = "15",
doi = "10.1002/(SICI)1097-4695(19990615)39:4<536::AID-NEU7>3.0.CO;2-J",
language = "English",
volume = "39",
pages = "536--546",
journal = "Developmental Neurobiology",
issn = "1932-8451",
publisher = "John Wiley and Sons Inc.",
number = "4",

}

Phosphatidylinositol 3-kinase-mediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I. / Ryu, Bo Rum; Ko, Hyuk Wan; Jou, Ilo; Noh, Jai Sung; Gwag, Byoung Joo.

In: Journal of Neurobiology, Vol. 39, No. 4, 15.06.1999, p. 536-546.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phosphatidylinositol 3-kinase-mediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I

AU - Ryu, Bo Rum

AU - Ko, Hyuk Wan

AU - Jou, Ilo

AU - Noh, Jai Sung

AU - Gwag, Byoung Joo

PY - 1999/6/15

Y1 - 1999/6/15

N2 - 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 μM N-methyl-D-aspartate or 40 μM 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 μM Fe2+ or 100 μM 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 uon the activation of PI 3- kinase.

AB - 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 μM N-methyl-D-aspartate or 40 μM 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 μM Fe2+ or 100 μM 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 uon the activation of PI 3- kinase.

UR - http://www.scopus.com/inward/record.url?scp=0006460824&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0006460824&partnerID=8YFLogxK

U2 - 10.1002/(SICI)1097-4695(19990615)39:4<536::AID-NEU7>3.0.CO;2-J

DO - 10.1002/(SICI)1097-4695(19990615)39:4<536::AID-NEU7>3.0.CO;2-J

M3 - Article

VL - 39

SP - 536

EP - 546

JO - Developmental Neurobiology

JF - Developmental Neurobiology

SN - 1932-8451

IS - 4

ER -