Donepezil promotes neurogenesis via Src signaling pathway in a rat model of chronic cerebral hypoperfusion.

Abstract Donepezil, a selective acetylcholinesterase (AchE) inhibitor, enhances stroke-induced neurogenesis within subventricular zone (SVZ). Src/Pyk-2 is one of the downstream pathways of acetylcholine receptors (AchRs), and has been shown to participate in the activation of fibroblast growth factor receptor (FGFR)/ epidermal growth factor receptor (EGFR) signaling in cancer cells. In this study, we investigated whether donepezil could promote SVZ neurogenesis in chronic cerebral hypoperfusion (CCH) injury via Src signaling pathway. In the bilateral carotid artery occlusion (2VO) rat model, we observed more nestin/5-bromo-2′-deoxyuridine (BrdU)-positive cells and doublecortin (DCX)/BrdU-positive cells in the SVZ than that in the sham group. Further, donepezil obviously improved neurologic function after 2VO, induced the greater number of SVZ proliferative NSCs and neuroblasts, and elevated levels of Src, p-FGFR1, p-EGFR, p-Akt and p-Raf in ipsilateral SVZ. Lastly, Src inhibitor KX-01 abolished the beneficial effects of donepezil in 2VO rats. These results suggest that donepezil could upregulate Src signaling pathway to enhance CCH-induced SVZ neurogenesis.