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Mechanisms of platelet‐derived growth factor‐mediated neuroprotection – implications in HIV dementia
Author(s) -
Peng Fuwang,
Dhillon Navneet K.,
Yao Honghong,
Zhu Xuhui,
Williams Rachel,
Buch Shilpa
Publication year - 2008
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2008.06444.x
Subject(s) - protein kinase b , neuroprotection , platelet derived growth factor receptor , pi3k/akt/mtor pathway , microbiology and biotechnology , phosphorylation , biology , apoptosis , growth factor , signal transduction , pharmacology , cancer research , chemistry , biochemistry , receptor
Platelet‐derived growth factor (PDGF) has been implicated in promoting survival and proliferation of immature neurons, and even protecting neurons from gp120‐induced cytotoxicity. However, the mechanisms involved in neuroprotection are not well understood. In the present study we demonstrate the role of phosphatidylinositol 3‐kinase (PI3K)/Akt signaling in PDGF‐mediated neuroprotection. Pharmacological inhibition of PI3K greatly reduced the ability of PDGF‐BB to block gp120 IIIB‐mediated apoptosis and cell death in human neuroblastoma cells. The role of Akt in PDGF‐mediated protection was further corroborated using a dominant‐negative mutant of Akt, which was able to block the protective effect of PDGF. We next sequentially examined the signals downstream of Akt in PDGF‐mediated protection in human neuroblastoma cells. In cells pretreated with PDGF prior to gp120 there was increased phosphorylation of both GSK‐3β and Bad, an effect that was inhibited by PI3‐kinase inhibitor. Nuclear translocation of NF‐κB, which lies downstream of GSK‐3β, however, remained unaffected in cells treated with PDGF. In addition to inducing phosphorylation of Bad, PDGF‐mediated protection also involved down‐regulation of the proapoptotic protein Bax. Furthermore, PDGF‐mediated protection also involved the inhibition of gp120‐induced release of mitochondrial cytochrome C. Our findings thus underscore the roles of both PI3K/Akt and Bcl family pathways in PDGF‐mediated neuroprotection.