Wang Shengran, Wang Sixuan, Wang Zhun, Dong Jinpeng, Zhang Mengxue, Wang Yongan, Wang Jianyu, Jia Beichen, Luo Yuan, Yin Yiqing
National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
CNS Neurosci Ther. 2024 May;30(5):e14716. doi: 10.1111/cns.14716.
Sevoflurane is a superior agent for maintaining anesthesia during surgical procedures. However, the neurotoxic mechanisms of clinical concentration remain poorly understood. Sevoflurane can interfere with the normal function of neurons and synapses and impair cognitive function by acting on α5-GABAAR.
Using MWM test, we evaluated cognitive abilities in mice following 1 h of anesthesia with 2.7%-3% sevoflurane. Based on hippocampal transcriptome analysis, we analyzed the differential genes and IL-6 24 h post-anesthesia. Western blot and RT-PCR were performed to measure the levels of α5-GABAAR, Radixin, P-ERM, P-Radixin, Gephyrin, IL-6, and ROCK. The spatial distribution and expression of α5-GABAAR on neuronal somata were analyzed using histological and three-dimensional imaging techniques.
MWM test indicated that partial long-term learning and memory impairment. Combining molecular biology and histological analysis, our studies have demonstrated that sevoflurane induces immunosuppression, characterized by reduced IL-6 expression levels, and that enhanced Radixin dephosphorylation undermines the microstructural stability of α5-GABAAR, leading to its dissociation from synaptic exterior and resulting in a disordered distribution in α5-GABAAR expression within neuronal cell bodies. On the synaptic cleft, the expression level of α5-GABAAR remained unchanged, the spatial distribution became more compact, with an increased fluorescence intensity per voxel. On the extra-synaptic space, the expression level of α5-GABAAR decreased within unchanged spatial distribution, accompanied by an increased fluorescence intensity per voxel.
Dysregulated α5-GABAAR expression and distribution contributes to sevoflurane-induced partial long-term learning and memory impairment, which lays the foundation for elucidating the underlying mechanisms in future studies.
七氟醚是手术过程中维持麻醉的一种优质药物。然而，临床浓度下的神经毒性机制仍知之甚少。七氟醚可通过作用于α5 - GABA A R干扰神经元和突触的正常功能并损害认知功能。
我们使用莫里斯水迷宫试验评估了用2.7% - 3%七氟醚麻醉1小时后小鼠的认知能力。基于海马转录组分析，我们在麻醉后24小时分析了差异基因和白细胞介素 - 6。进行蛋白质免疫印迹法和逆转录 - 聚合酶链反应以测量α5 - GABA A R、根蛋白、磷酸化埃兹蛋白 - 根蛋白 - 膜突蛋白、磷酸化根蛋白、gephyrin、白细胞介素 - 6和Rho相关卷曲螺旋形成蛋白激酶的水平。使用组织学和三维成像技术分析α5 - GABA A R在神经元胞体上的空间分布和表达。
莫里斯水迷宫试验表明存在部分长期学习和记忆损伤。结合分子生物学和组织学分析，我们的研究表明七氟醚诱导免疫抑制，其特征为白细胞介素 - 6表达水平降低，并且根蛋白去磷酸化增强破坏了α5 - GABA A R的微观结构稳定性，导致其从突触外部解离，从而在神经元细胞体内α5 - GABA A R表达中产生无序分布。在突触间隙，α5 - GABA A R的表达水平保持不变，空间分布变得更紧密，每体素的荧光强度增加。在突触外空间，α5 - GABA A R的表达水平在空间分布不变的情况下降低，同时每体素的荧光强度增加。
α5 - GABA A R表达和分布失调导致七氟醚诱导的部分长期学习和记忆损伤，这为未来研究阐明潜在机制奠定了基础。
