Exp Mol Med.  2010 Aug;42(8):583-595. 10.3858/emm.2010.42.8.060.

Neuroprotection signaling pathway of nerve growth factor and brain-derived neurotrophic factor against staurosporine induced apoptosis in hippocampal H19-7 cells

• Nguyen TL
• Kim CK
• Cho JH
• Lee KH
• Ahn JY

• KMID: 1104385
• DOI: http://doi.org/10.3858/emm.2010.42.8.060

Abstract

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.

Keyword

brain-derived neurotrophic factor; cell survival; nerve growth factors; phosphatidylinositol 3 kinase; protein kinase B; receptor, trkA

MeSH Terms

Animals
Apoptosis/*drug effects
Brain-Derived Neurotrophic Factor/*metabolism
Cell Line
Cell Survival/drug effects
Cytoprotection/*drug effects
Gene Knockdown Techniques
Hippocampus/*cytology
Nerve Growth Factor/*metabolism
Neurons/*cytology/drug effects/metabolism
PC12 Cells
Proto-Oncogene Proteins c-akt/metabolism
Rats
Receptors, Nerve Growth Factor/metabolism
Signal Transduction/drug effects
Staurosporine/*pharmacology