Abstract
BACKGROUND: 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. OBJECTIVES: This study aimed to investigate the mechanisms of melatonin against sevoflurane-induced neurotoxicity. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.