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| 海马RhoA-ROCK2通路在老年小鼠术后认知功能障碍中的作用 |
| Roles of hippocampal RhoA-ROCK2 signaling in aged mice with postoperative cognitive dysfunction |
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| DOI：10.12089/jca.2018.06.013 |
| 中文关键词: 术后认知功能障碍 老年小鼠 海马 RhoA-ROCK2通路 突触重塑 |
| 英文关键词: Postoperative cognitive dysfunction Aged mice Hippocampus RhoA-ROCK2 signaling pathway Synaptic plasticity |
| 基金项目:国家自然科学基金（81471105） |
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| 中文摘要: |
目的 探讨海马RhoA-ROCK2通路在老年小鼠术后认知功能障碍(postoperative cognitive dysfunction, POCD)中的作用及潜在机制。
方法 采用异氟醚麻醉+腹腔探查术建立POCD模型。18月龄雄性C57BL/6小鼠48只,随机均分为四组:对照+生理盐水组(CS组)、对照+法舒地尔(Rho激酶抑制剂)组(CF组)、异氟醚麻醉+腹腔探查术+生理盐水组(SS组)及异氟醚麻醉+腹腔探查术+法舒地尔组(SF组)。水迷宫训练开始前2 h至行为学结束前2 h，每天腹腔注射法舒地尔25 mg/kg或等容量生理盐水,连续注射13 d。手术前5 d起行水迷宫训练,术后第1、3、7 天分别行水迷宫定位航行测试，第7天定位航行测试后4 h行空间探索测试。最后一次行为学测试后1 h,取小鼠海马及全脑组织,检测海马ROCK2、Rho-GDIα、p-cofilin、cofilin、F-actin、G-actin蛋白含量、RhoA活性及CA1区神经元树突棘数目。
结果 水迷宫训练阶段,四组游泳速度及逃避潜伏期差异无统计学意义。与CS和CF组比较,术后第1、3、7天SS组逃避潜伏期明显延长，术后第7天平台象限停留时间明显缩短，原平台穿越次数明显减少,海马内RhoA活性及ROCK2蛋白含量明显增加，Rho-GDIα蛋白含量、p-cofilin/coflin、F-actin/G-actin及CA1区神经元树突棘数目明显减少(P<0.05);与SS组比较,术后第1、3、7天SF组逃避潜伏期明显缩短，术后第7天平台象限停留时间明显延长，原平台穿越次数明显增加，海马内RhoA活性及ROCK2蛋白含量明显降低、Rho-GDIα蛋白含量、p-cofilin/coflin、F-actin/G-actin及CA1区神经元树突棘数目明显增多(P<0.05)。
结论 术后认知功能障碍老年小鼠海马内RhoA-ROCK2通路活性增加;法舒地尔可改善术后老年小鼠空间记忆损害,其作用机制可能与抑制RhoA-ROCK2通路,增强actin动力学和突触重塑有关。 |
| 英文摘要: |
Objective To investigate the roles of hippocampal RhoA-ROCK2 signaling on postoperative cognitive function (POCD) in aged mice, and further to explore the potential underling mechanism.
Methods A POCD model was established by isoflurane anesthesia+abdominal exploration. Forty-eight male C57BL/6 mice 18-month-old were randomly divided into four groups: group control+saline (group CS), group control+fasudil (a Rho-kinase inhibitor, CF), group isoflurane anesthesia+laparotomy surgery+saline (group SS), and group isoflurane anesthesia+laparotomy surgery+fasudil (group SF). Animals were subjected to an administration of fausdil 25 mg/kg or isochoric saline via intraperitoneal injection once daily for 13 consecutive days, injection was given from 2 h before the training session of morris water maze to the last behavioral test. The train of morris water maze was performed at 5 d before operation. The tests of place navigation were exhibited at 1, 3 and 7 d after operation, respectively. The test of spatial exploration was exhibited 4 h after the last place navigation test. The hippocampus and whole brain were harvested 1 h after the last behavioral test. Western blot was used to detect the expressions of hippocampal ROCK2, Rho-GDIα, p-cofilin, cofilin, F-actin, and G-actin. RhoA activation assay kit was used to detect the activity of RhoA. Golgi staining was applied to measure the changes of dendritic spines in hippocampal CA1 subfield.
Results In the training sessions of morris water maze, no significantly differences were observed in the swim speed and escape latency in each group. Compared with groups CS and CF, the escape latency was significantly increased, time spent in the target quadrant and crossing times were significantly decreased, the activity of RhoA and the content of ROCK2 were significantly increased, the expression of Rho-GDIα, p-cofilin/coflin, F-actin/G-actin, and the number of dendritic spine in CA1 subfield were significantly decreased in group SS (P < 0.05). Compared with group SS, the escape latency was significantly decreased, time spent in the target quadrant and crossing times were significantly increased, the activity of RhoA and the content of ROCK2 were significantly decreased, the expression of Rho-GDIα, p-cofilin/coflin, F-actin/G-actin, and the number of dendritic spine in CA1 subfield were significantly increased in group SF (P < 0.05).
Conclusion Over-activated of hippocampal RhoA-ROCK2 signaling participated in POCD-aged mice. Fasudil, a Rho kinase inhibitor, may attenuate the spatial cognitive impairments in aged mice after surgery via inhibiting hippocampal RhoA-ROCK2 signaling and enhancing actin dynamic and synaptic plasticity. |
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