Donepezil promotes neurogenesis via Src signaling pathway in a rat model of chronic cerebral hypoperfusion
Donepezil promotes neurogenesis via Src signaling pathway in a rat model of chronic cerebral hypoperfusion
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多奈哌齐通过 Src 信号通路促进慢性脑低灌注大鼠模型的神经发生
DOI：
10.1016/j.brainres.2020.146782
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发表时间：
2020-06-01
期刊：
影响因子：
2.9
通讯作者：
Wang，Jianping
中科院分区：
文献类型：
--
作者：
Man，Jiang;Cui，Kefei;Wang，Jianping
多奈哌齐是一种选择性乙酰胆碱酯酶 (AchE) 抑制剂，可增强脑室下区 (SVZ) 内中风诱发的神经发生。 Src/Pyk-2是乙酰胆碱受体(AchRs)的下游通路之一，已被证明参与癌细胞中成纤维细胞生长因子受体(FGFR)/表皮生长因子受体(EGFR)信号传导的激活。在本研究中，我们研究了多奈哌齐是否可以通过Src信号通路促进慢性脑灌注不足（CCH）损伤中的SVZ神经发生。在双侧颈动脉闭塞（2VO）大鼠模型中，我们在 SVZ 中观察到比假手术组更多的巢蛋白/5-溴-2′-脱氧尿苷（BrdU）阳性细胞和双皮质素（DCX）/BrdU 阳性细胞。此外，多奈哌齐明显改善2VO后的神经功能，诱导更多数量的SVZ增殖性NSC和神经母细胞，并升高同侧SVZ中Src、p-FGFR1、p-EGFR、p-Akt和p-Raf的水平。最后，Src 抑制剂 KX-01 消除了多奈哌齐对 2VO 大鼠的有益作用。这些结果表明，多奈哌齐可以上调 Src 信号通路，从而增强 CCH 诱导的 SVZ 神经发生。
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.