Mechanisms of platelet-derived growth factor-mediated neuroprotection - Implications in HIV dementia

Fuwang Peng, Navneet K. Dhillon, Honghong Yao, Xuhui Zhu, Rachel Williams, Shilpa Buch

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1255-1264
Number of pages10
JournalEuropean Journal of Neuroscience
Volume28
Issue number7
DOIs
StatePublished - Oct 2008

Keywords

  • Gp120
  • HIV dementia
  • Neuronal signaling
  • Neurons
  • PDGF

ASJC Scopus subject areas

  • Neuroscience(all)

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