艾司氯胺酮调节PI3K/Akt/mTOR信号通路对抑郁症大鼠认知障碍的影响

doi:10.3969/j.issn.1006-6233.2024.07.02

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Abstract Objective: To investigate the effect of esketamine (ISLAT) on cognitive impairment in rats with depression by regulating the PI3K/Akt/mTOR signaling pathway. Methods: Rats were randomly separated into CK group, Model group, ISLAT low-dose (ISLAT-L) group, ISLAT high-dose (ISLAT-H) group, and ISLAT-H+LY294002 (PI3K pathway inhibitor) group, all rats intraperitoneally injected with the corresponding drug for once a day for 3 weeks. The open field experiment, sugar water preference experiment, and forced swimming experiment were applied to evaluate the depressive behavior and cognitive function of rats. ELISA method was applied to detect the levels of TNF-α, IL-10, and IL-6 in serum, and brain-derived neurotrophic factor (BDNF), norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in hippocampal tissue. HE staining was applied to observe hippocampal tissue damage in rats. TUNEL was applied to detect apoptosis of hippocampal neurons in rats. Western blot was applied to detect the expression of Cleaved-caspase-3, p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR proteins in rat hippocampal tissue. Results: Compared with the CK group, the model group showed great damage to the morphology of hippocampal neurons in rats, the number of standing times, sucrose water consumption, serum IL-10 level, BDNF, NE, DA, 5-HT levels in hippocampal tissue, p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR protein expression levels were greatly reduced, the swimming immobility time, serum TNF-α and IL-6 levels, neuronal apoptosis rate, and Cleaved-caspase-3 protein expression level were greatly increased (P<0.05). Compared with the Model group, the morphology of hippocampal neurons in the ISLAT-L and ISLAT-H groups showed great improvement, the number of standing times, sucrose water consumption, serum IL-10 level, BDNF, NE, DA, 5-HT levels in hippocampal tissue, p-PI3K/PI3K, p-Akt/Akt, and p-mTOR/mTOR protein expression levels were greatly increased, the swimming immobility time, serum TNF-α and IL-6 levels, neuronal apoptosis rate, and Cleaved-caspase-3 protein expression level were greatly reduced (P<0.05). LY294002 was able to alleviate the cognitive improvement effect of ISLAT on depression rats (P<0.05). Conclusion: ISLAT can alleviate inflammation, reduce nerve tissue damage and neuronal apoptosis, and improve depression symptoms in rats by activating the PI3K/Akt/mTOR signaling pathway.

Key words： Esketamine PI3K/Akt/mTOR signaling pathway Depression Cognitive impairment

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http://www.hbyxzzs.cn/EN/10.3969/j.issn.1006-6233.2024.07.02 OR http://www.hbyxzzs.cn/EN/Y2024/V30/I7/1062

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