Fasudil Alleviates Postoperative Neurocognitive Disorders in Mice by Downregulating the Surface Expression of α5GABAAR in Hippocampus

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-11-03 DOI:10.1111/cns.70098

Jinpeng Dong, Zhun Wang, Lixuan Li, Mengxue Zhang, Sixuan Wang, Yuan Luo, Ying Dong, Xiaokun Wang, Yongan Wang, Kaiyuan Wang, Yiqing Yin

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Abstract

Aim

Postoperative neurocognitive disorder (PND) refers to the cognitive impairment experienced by patients after surgery. As a target of sevoflurane, a kind of inhalation anesthetic, the balance of the GABAergic system can be disrupted during the perioperative period. In this study, we explored the promoting effect of abnormal elevation of the α5 subtype of γ-aminobutyric acid type A (GABAA) receptors caused by sevoflurane and surgical trauma on PND, as well as the therapeutic effect of fasudil on PND.

Methods

Eight-week-old mice were pretreated with fasudil, and after 10 days, sevoflurane-induced femoral fracture surgery was performed to establish an animal model of PND. The Morris water maze and fear conditioning tests were used to evaluate PND induced by this model. Biochemical and electrophysiological analyses were conducted to assess the protective effect of fasudil on the GABAergic system.

Results

Following artificial fracture, the hippocampus-dependent memory was damaged in these mice. Fasudil pretreatment, however, ameliorated cognitive function impairment in mice induced by sevoflurane and surgery. Mechanistically, fasudil was found to restore the increased hippocampus expression and function of α5GABAARs in mice with PND. In addition, pretreatment with Fasudil inhibited the enhancement in the calcium ion concentration and phosphorylation of Camk2, as well as the activation of the Radixin pathway which led to increased phosphorylation of the ERM family in the hippocampal CA1 region of the PND model.

Conclusion

Preadministration of fasudil improved postoperative cognitive function in PND mice by inhibiting the activation of Camk2 and Radixin pathways and finally downregulating the surface expression of α5GABAAR in hippocampus neurons.

Abstract Image

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法舒地尔通过下调海马中α5GABAAR的表面表达缓解小鼠术后神经认知障碍

目的：术后神经认知障碍（PND）是指患者在手术后出现的认知障碍。七氟醚是一种吸入麻醉剂，作为七氟醚的作用靶点，GABA能系统的平衡在围手术期会被打破。本研究探讨了七氟烷和手术创伤引起的γ-氨基丁酸A型（GABAA）受体α5亚型异常升高对PND的促进作用，以及法舒地尔对PND的治疗作用：方法：用法舒地尔预处理8周龄小鼠，10天后进行七氟醚诱导的股骨骨折手术，建立PND动物模型。采用莫里斯水迷宫和恐惧条件反射试验评估该模型诱导的PND。生化和电生理分析评估了法舒地尔对GABA能系统的保护作用：结果：人工骨折后，这些小鼠的海马依赖性记忆受损。然而，法舒地尔预处理可改善七氟醚和手术引起的小鼠认知功能损伤。从机理上讲，法舒地尔可恢复PND小鼠海马中增加的α5GABAARs表达和功能。此外，法舒地尔还能抑制钙离子浓度的升高和Camk2的磷酸化，以及Radixin通路的激活，从而导致PND模型海马CA1区ERM家族磷酸化的增加：结论：法舒地尔通过抑制Camk2和Radixin通路的激活，最终下调海马神经元中α5GABAAR的表面表达，改善了PND小鼠的术后认知功能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.