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

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 NF kappa B, which was also important for neuroprotection. Akt inhibition prevented NF kappa B binding, suggesting a role for Akt in SCF-induced NF kappa B. Pharmacological inhibition of NF kappa B or dominant negative I kappa B also prevented neuroprotection by SCF. SCF up-regulated the anti-apoptotic genes, bcl-2 and bcl-xL in an NF kappa B-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 NF kappa B-mediated gene transcription. SCF represents a novel therapeutic target in the treatment of neurodegenerative disease.