Neuroprotection by stem cell factor in rat cortical neurons involves AKT and NFκB

Krishnan M. Dhandapani, F. Marlene Wade, Chandramohan Wakade, Virendra B. Mahesh, Darrell W. Brann

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Stem cell factor (SCF) is a highly expressed cytokine in the central nervous system. In the present study, we demonstrate a neuroprotective role for SCF and its tyrosine kinase receptor, c-kit, against camptothecin-induced apoptosis and glutamate excitotoxicity in rat cortical neurons. This protection was blocked by pharmacological or molecular inhibition of either the MEK/ERK or PI3K/Akt signaling pathways. The importance of these pathways was further confirmed by the activation of both ERK, in a MEK-dependent manner, and Akt, via PI3K. Activation of Akt increased the binding of the p50 and p65 subunits of NKκB, which was also important for neuroprotection. Akt inhibition prevented NFκB binding, suggesting a role for Akt in SCF-induced NFκB. Pharmacological inhibition of NFκB or dominant negative IκB also prevented neuroprotection by SCF. SCF up-regulated the anti-apoptotic genes, bcl-2 and bcl-xL in an NFκB-dependent manner. Together, these findings demonstrate a neuroprotective role for SCF in cortical neurons, an effect that was mediated by Akt and ERK, as well as NFκB-mediated gene transcription. SCF represents a novel therapeutic target in the treatment of neurodegenerative disease.

Original languageEnglish (US)
Pages (from-to)9-19
Number of pages11
JournalJournal of Neurochemistry
Volume95
Issue number1
DOIs
StatePublished - Oct 2005

Keywords

  • Akt
  • Mitogen-activated protein kinase
  • NFκB
  • Neuroprotection
  • Stem cell factor
  • c-Kit

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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