Shen Qihong, Jiang Yanyu, Jia Xiaoyu, Zhou Xuyan, Zhou Qing-He
Department of Anesthesiology, Affiliated Hospital of Jiaxing University, Jiaxing, China.
Department of Anesthesia Medicine, Bengbu Medical College, Bengbu, China.
Iran J Pharm Res. 2023 Jan 24;21(1):e133971. doi: 10.5812/ijpr-133971. eCollection 2022 Dec.
Postoperative cognitive dysfunction (POCD) can be described as a clinical phenomenon characterized by cognitive impairment in patients, particularly elderly patients, after anesthesia and surgery. Researchers have focused on the probable effect of general anesthesia drugs on cognitive functioning status in older adults. Melatonin is an indole-type neuroendocrine hormone with broad biological activity and potent anti-inflammatory, anti-apoptotic, and neuroprotective effects. This study investigated the effects of melatonin on cognitive behavior in aged mice anesthetized with sevoflurane. In addition, melatonin's molecular mechanism was determined.
This study aimed to investigate the mechanisms of melatonin against sevoflurane-induced neurotoxicity.
A total of 94 aged C57BL/6J mice were categorized into different groups, namely control (control + melatonin (10 mg/kg)), sevoflurane (sevoflurane + melatonin (10 mg/kg)), sevoflurane + melatonin (10 mg/kg) + phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) inhibitor LY294002 (30 mg/kg), and sevoflurane + melatonin (10 mg/kg) + mammalian target of rapamycin (mTOR) inhibitor (10 mg/kg). The open field and Morris water maze tests were utilized to assess the neuroprotective effects of melatonin on sevoflurane-induced cognitive impairment in aged mice. The expression levels of the apoptosis-linked proteins, PI3K/Akt/mTOR signaling pathway, and pro-inflammatory cytokines in the brain's hippocampus region were determined using the Western blotting technique. The apoptosis of the hippocampal neurons was observed using the hematoxylin and eosin staining technique.
Neurological deficits in aged, sevoflurane-exposed mice were significantly decreased after melatonin treatment. Mechanistically, melatonin treatment restored sevoflurane-induced down-regulated PI3K/Akt/mTOR expression and significantly attenuated sevoflurane-induced apoptotic cells and neuroinflammation.
The findings of this study have highlighted the neuroprotective effect of melatonin on sevoflurane-induced cognitive impairment via regulating the PI3K/Akt/mTOR pathway, which might be effective in the clinical treatment of elderly patients with anesthesia-induced POCD.
术后认知功能障碍（POCD）可被描述为一种临床现象，其特征为患者尤其是老年患者在麻醉和手术后出现认知障碍。研究人员一直关注全身麻醉药物对老年人认知功能状态的可能影响。褪黑素是一种具有广泛生物活性以及强大抗炎、抗凋亡和神经保护作用的吲哚类神经内分泌激素。本研究调查了褪黑素对七氟醚麻醉的老年小鼠认知行为的影响。此外，还确定了褪黑素的分子机制。
本研究旨在探讨褪黑素对抗七氟醚诱导的神经毒性的机制。
将总共94只老年C57BL/6J小鼠分为不同组，即对照组（对照 + 褪黑素（10 mg/kg））、七氟醚组（七氟醚 + 褪黑素（10 mg/kg））、七氟醚 + 褪黑素（10 mg/kg） + 磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）抑制剂LY294002（30 mg/kg）组，以及七氟醚 + 褪黑素（10 mg/kg） + 雷帕霉素靶蛋白（mTOR）抑制剂（10 mg/kg）组。采用旷场试验和莫里斯水迷宫试验评估褪黑素对七氟醚诱导的老年小鼠认知障碍的神经保护作用。使用蛋白质印迹技术测定大脑海马区凋亡相关蛋白、PI3K/Akt/mTOR信号通路和促炎细胞因子的表达水平。使用苏木精和伊红染色技术观察海马神经元的凋亡情况。
褪黑素治疗后，暴露于七氟醚的老年小鼠的神经功能缺损明显减少。从机制上讲，褪黑素治疗恢复了七氟醚诱导的PI3K/Akt/mTOR表达下调，并显著减轻了七氟醚诱导的凋亡细胞和神经炎症。
本研究结果突出了褪黑素通过调节PI3K/Akt/mTOR途径对七氟醚诱导的认知障碍的神经保护作用，这可能对临床治疗老年麻醉诱导的POCD患者有效。
