Department of Anesthesiology and Operation, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330052, China.
Department of Gynaecology and Obstetrics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
J Mol Neurosci. 2024 Jul 17;74(3):69. doi: 10.1007/s12031-024-02243-1.
The objective of this investigation was to examine the impact of multiple exposures to general anesthesia (GA) with sevoflurane on the offspring of pregnant mice, as well as to elucidate the underlying mechanism. Neurodevelopmental assessments, including various reflexes and behavioral tests, were conducted on the offspring in the GA group to evaluate neuronal cell development. Furthermore, neonatal mouse neuronal cells were isolated and transfected with a high-expression CREB vector (pcDNA3.1-CREB), followed by treatment with sevoflurane (0.72 mol/L), ZD7288 (50 μmol/L), and KN-62 (10 μmol/L), or a combination of these compounds. The expression of relevant genes was then analyzed using qRT-PCR and western blot techniques. In comparison to the sham group, neonatal mice in the GA group exhibited significantly prolonged latencies in surface righting reflex, geotaxis test, and air righting reflex. Furthermore, there was a notable deceleration in the development of body weight and tail in the GA group. These mice also displayed impairments in social ability, reduced reciprocal social interaction behaviors, diminished learning capacity, and heightened levels of anxious behaviors. Additionally, synaptic trigger malfunction was observed, along with decreased production of c-Fos and neurotrophic factors. Sevoflurane was found to notably decrease cellular c-Fos and neurotrophic factor production, as well as the expression of HCN2 and CaMKII/CREB-related proteins. The inhibitory effects of sevoflurane on HCN2 or CaMKII channels were similar to those observed with ZD7288 or KN-62 inhibition. However, overexpression of CREB mitigated the impact of sevoflurane on neuronal cells. Repetitive exposure to sevoflurane general anesthesia while pregnant suppresses the CaMKII/CREB pathway, leading to the development of autism-like characteristics in offspring mice through the reduction of HCN2 expression.
本研究旨在探讨多次吸入七氟醚全身麻醉（GA）对孕鼠后代的影响，并阐明其潜在机制。对 GA 组后代进行神经发育评估，包括各种反射和行为测试，以评估神经元细胞发育。此外，分离新生小鼠神经元细胞，并转染高表达 CREB 载体（pcDNA3.1-CREB），然后用七氟醚（0.72 mol/L）、ZD7288（50 μmol/L）和 KN-62（10 μmol/L）或这些化合物的组合处理。然后使用 qRT-PCR 和 Western blot 技术分析相关基因的表达。与假手术组相比，GA 组新生小鼠的表面翻正反射、趋地反射和空气翻正反射潜伏期明显延长。此外，GA 组体重和尾巴的发育明显减慢。这些小鼠还表现出社交能力受损、互惠社交互动行为减少、学习能力下降和焦虑行为增加。此外，还观察到突触触发功能障碍，c-Fos 和神经营养因子生成减少。七氟醚显著降低细胞 c-Fos 和神经营养因子的产生，以及 HCN2 和 CaMKII/CREB 相关蛋白的表达。七氟醚对 HCN2 或 CaMKII 通道的抑制作用与 ZD7288 或 KN-62 抑制相似。然而，CREB 的过表达减轻了七氟醚对神经元细胞的影响。怀孕期间反复接触七氟醚全身麻醉会抑制 CaMKII/CREB 通路，通过降低 HCN2 的表达，导致子代小鼠出现类似自闭症的特征。
