Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei 230061, Anhui Province, China; Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China.
Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei 230061, Anhui Province, China.
Brain Res Bull. 2023 Nov;204:110809. doi: 10.1016/j.brainresbull.2023.110809. Epub 2023 Nov 4.
Sevoflurane, a commonly administered inhaled anesthetic, is found to induce synaptic and mitochondrial damage in neonatal mice. Mitochondrial membrane potential (MMP) changes, mediated by Cyclophilin D (CypD), are implicated in mitochondrial function. Melatonin, known for its significant neuroprotective properties, was investigated in this study to elucidate its mechanisms in mitigating the cognitive impairment caused by sevoflurane.
The mice were categorized into several groups, including the control, vehicle, sevoflurane, vehicle plus sevoflurane, and melatonin plus sevoflurane groups. From postnatal day 6 to day 8, the mice were administered inhaled sevoflurane or intraperitoneal melatonin. MMP and reactive oxygen species (ROS) were measured using appropriate detection kits. The protein expression levels of PSD95, Synapsin Ⅰ, and CypD in the hippocampus were analyzed through western blotting in acute and prolonged terms. Immunofluorescence staining was used to assess the co-localizations of PSD95 or CypD in parvalbumin (PV) neurons. Cognitive ability was evaluated through novel object recognition, social interaction experiment, and the Morris water maze.
The findings revealed that repeated exposure to sevoflurane in neonatal mice resulted in cognitive and synaptic impairment. Furthermore, melatonin administration suppressed the ROS and CypD protein expression, enhanced the MMP in mitochondria and synaptic protein expression in PV neurons, and ameliorated cognitive deficits.
Melatonin alleviated sevoflurane-induced cognitive deficits by suppressing CypD and promoting synaptic development in hippocampal PV neurons. These results provide valuable insights into a promising therapeutic approach for preventing neurotoxic injuries caused by general anesthetics.
七氟醚是一种常用的吸入性麻醉剂，已被发现可导致新生小鼠的突触和线粒体损伤。环孢素 D（CypD）介导的线粒体膜电位（MMP）变化与线粒体功能有关。褪黑素因其显著的神经保护特性而在本研究中被研究，以阐明其在减轻七氟醚引起的认知障碍中的机制。
将小鼠分为对照组、载体组、七氟醚组、载体加七氟醚组和褪黑素加七氟醚组。从出生后第 6 天到第 8 天，给小鼠吸入七氟醚或腹腔内注射褪黑素。使用适当的检测试剂盒测量 MMP 和活性氧（ROS）。通过 Western blot 分析急性和长期海马 PSD95、Synapsin Ⅰ和 CypD 的蛋白表达水平。免疫荧光染色用于评估 PSD95 或 CypD 在 Parvalbumin（PV）神经元中的共定位。通过新物体识别、社交互动实验和 Morris 水迷宫评估认知能力。
研究结果表明，反复暴露于新生小鼠的七氟醚会导致认知和突触损伤。此外，褪黑素的给药抑制了 ROS 和 CypD 蛋白表达，增强了线粒体和 PV 神经元中的突触蛋白表达，改善了认知缺陷。
褪黑素通过抑制 CypD 和促进海马 PV 神经元中的突触发育来减轻七氟醚引起的认知障碍。这些结果为预防全身麻醉引起的神经毒性损伤提供了有价值的治疗方法。
