Neuroprotection signaling pathway of nerve growth factor and brain-derived neurotrophic factor against staurosporine induced apoptosis in hippocampal H19-7/IGF-IR [corrected].
Neurotrophins protect neurons against excitotoxicity; however the signaling mechanisms for this protection remain to be fully elucidated. Here we report that activation of the phosphatidyl inositol 3 kinase (PI3K)/Akt pathway is critical for protection of hippocampal cells from staurosporine (STS) induced apoptosis, characterized by nuclear condensation and activation of the caspase cascade. Both nerve growth factor (NGF) and brain-derived growth factor (BDNF) prevent STS-induced apoptotic morphology and caspase-3 activity by upregulating phosphorylation of the tropomyosin receptor kinase (Trk) receptor. Inhibition of Trk receptor by K252a altered the neuroprotective effect of both NGF and BDNF whereas inhibition of the p75 neurotrophin receptor (p75NTR) had no effect. Impairment of the PI3K/Akt pathway or overexpression of dominant negative (DN)-Akt abolished the protective effect of both neurotrophins, while active Akt prevented cell death. Moreover, knockdown of Akt by si-RNA was able to block the survival effect of both NGF and BDNF. Thus, the survival action of NGF and BDNF against STS-induced neurotoxicity was mediated by the activation of PI3K/Akt signaling through the Trk receptor.
Nguyen
Truong L X
TL
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.
Kim
Chung Kwon
CK
Cho
Jun-Hee
JH
Lee
Kyung-Hoon
KH
Ahn
Jee-Yin
JY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology*; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology*
D019208:Brain-Derived Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D020932:Nerve Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D019311:Staurosporine