Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis
Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis
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DOI：
10.1016/j.cbi.2008.04.004
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发表时间：
2008-09-25
影响因子：
5.1
通讯作者：
Ogura, Hiroo
中科院分区：
文献类型：
--
作者：
Kotani, Sadaharu;Yamauchi, Toshihiko;Ogura, Hiroo
盐酸多奈哌齐是一种有效的选择性乙酰胆碱酯酶抑制剂，已用于治疗阿尔茨海默病，其中观察到胆碱能功能障碍。最近，有报道称成年大鼠内侧间隔胆碱能核变性抑制了海马齿状回（DG）的神经发生。然后，我们确定激活脑胆碱能系统的多奈哌齐是否可以调节正常大鼠的海马神经发生。注射5'-溴-2'-脱氧尿苷（BrdU）来标记分裂细胞后，我们口服多奈哌齐（0.5或2 mg/kg），每天一次，持续4周。在另一组中，我们进行了为期 4 周的皮下输注东莨菪碱（0.75 或 3 毫克/天），一种毒蕈碱乙酰胆碱受体阻滞剂。据报道，我们在本研究中使用的多奈哌齐和东莨菪碱的剂量分别可以激活和抑制脂肪中的胆碱能活性。药物治疗完成一天后，处死动物，并进行免疫组织化学分析。与媒介物处理的对照相比，多奈哌齐增加了 DG 中 BrdU 阳性细胞的数量，但东莨菪碱减少了。这两种药物对神经元标记物 NeuN 也呈阳性的 BrdU 阳性细胞的百分比以及 DG 中增殖细胞核抗原阳性细胞的数量均没有任何影响。这些结果表明，多奈哌齐增强而东莨菪碱抑制DG中新生神经元的存活，而不影响神经祖细胞的增殖和神经元分化。我们还发现，长期治疗多奈哌齐可增强 DG 中参与细胞存活的 cAMP 反应元件结合蛋白 (CREB) 的磷酸化，而东莨菪碱可抑制磷酸化。这些结果表明多奈哌齐通过 CREB 信号传导激活中枢胆碱能传递并增强 DG 中新生神经元的存活。 (C) 2008 Elsevier Ireland Ltd. 保留所有权利。
Donepezil hydrochloride is a potent and selective acetylcholinesterase inhibitor and has been treated for Alzheimer's disease, in which the cholinergic dysfunction is observed. Recently, the degeneration of medial septal cholinergic nuclei in adult rat suppressed the neurogenesis in hippocampal dentate gyrus (DG) was reported. Then, we determined whether donepezil which activated the brain cholinergic system could modulate hippocampal neurogenesis in normal rats. After the injection of 5'-bromo-2'-deoxyuridine (BrdU) to label dividing cells, we orally treated with donepezil (0.5 or 2 mg/kg) once a day for 4 weeks. In the other group, we performed 4-week Subcutaneous infusion of scopolamine (0.75 or 3 mg/day), a muscarinic acetylcholine receptor blocker. The doses of donepezil and scopolamine we used in this study were reported to activate and inhibit cholinergic activity in Fats, respectively. One day after the completion of drug treatment, the animals were sacrificed, and immunohistochemical analysis was performed. Donepezil increased, but scopolamine decreased, the number of BrdU-positive cells in the DG as compared with the vehicle-treated control. Neither drug had any effects on the percentage of BrdU-positive cells that were also positive for a neuronal marker NeuN, nor the number of proliferating cell nuclear antigen-positive cells in the DG. These results indicate that donepezil enhances and scopolamine suppresses the Survival of newborn neurons in the DG without affecting the proliferation of neural progenitor cell and the neuronal differentiation. We also found that chronic treatment of donepezil enhanced, and scopolamine Suppressed phosphorylation of cAMP response element binding protein (CREB), which was involved in cell survival, in the DG. These results suggest that donepezil activates the central cholinergic transmission and enhances the survival of newborn neurons in the DG via CREB signaling. (C) 2008 Elsevier Ireland Ltd. All rights reserved.