术后认知功能减退(POCD)是老年人手术及麻醉后常见的并发症。然而,POCD的潜在机制仍然模棱两可,目前可用的治疗措施有限。据报道,氯胺酮可减弱心脏手术后的POCD。在这里,我们试图确定esketamine(氯胺酮的S-对映异构体)对POCD的影响以及可能的分子机制。
我们在老年SD大鼠(24个月)中使用探查性剖腹手术模型研究了艾氯胺酮(10mg/kg)对POCD的影响。开放领域,新颖的物体识别,和莫里斯水迷宫测试在手术后第30天进行。术后24h或30d,采集海马和腹内侧前额叶皮质(vmPFC)的脑组织,并进行组织病理学和分子生物学分析.在体外实验中,将海马和vmPFC的原代星形胶质细胞暴露于脂多糖(LPS),以研究POCD过程中星形胶质细胞的病理变化。
我们的结果表明,剖腹探查术可引起明显的认知和记忆下降,伴随着A2型星形胶质细胞表型丧失和神经元Aβ-42,星形胶质细胞GABA的表达增加,干扰素基因(STING)和TANK结合激酶1(TBK1)的刺激物。此外,LPS暴露显著降低线粒体膜电位,上调细胞凋亡相关蛋白水平,包括裂解的caspase-1和IL-18。值得注意的是,用艾氯胺酮治疗可在体内和体外逆转这些异常。然而,ADU-S100,一种特殊的STING激活器,在一定程度上抑制了艾氯胺酮的保护作用。最后,C-176,STING的拮抗剂,进一步增强了艾氯胺酮对POCD的保护作用。
我们的研究结果表明,艾氯胺酮可以通过抑制STING/TBK1信号通路减轻手术诱导的大鼠POCD。
Postoperative cognitive decline (POCD) is a common complication after surgery and anesthesia among the elderly. Yet the potential mechanism of POCD remains ambiguous, with limited therapeutic measures currently available. Ketamine has been reported to attenuate POCD after cardiac surgery. Herein, we tried to determine the effect of esketamine (the S-enantiomer of ketamine) on POCD and the possible molecular mechanisms.
We investigated the effects of esketamine (10 mg/kg) on POCD using an exploratory laparotomy model in aged SD rats (24 months). Open field, novel object recognition, and morris water maze tests were performed on day 30 post-surgery. 24 h or 30 d post-surgery, brain tissue from the hippocampus and ventromedial prefrontal cortex (vmPFC) was harvested and subjected to histopathology and molecular biology analysis. During the in vitro experiment, primary astrocytes from the hippocampus and vmPFC were exposed to lipopolysaccharide (LPS) to investigate the pathological changes in astrocytes during the process of POCD.
Our results indicated that exploratory laparotomy could induce significant cognitive and memory decline, accompanied by A2-type astrocytes phenotype loss and increased expression of neuron Aβ-42, astrocytes GABA, stimulator of interferon genes (STING) and TANK-binding kinase 1 (TBK1). In addition, LPS exposure significantly decreased the mitochondrial membrane potential and upregulated the level of pyroptosis-associated proteins, including cleaved caspase-1 and IL-18. Notably, treatment with esketamine reversed these abnormalities in vivo and vitro. However, ADU-S100, a special STING activator, suppressed the protective effects of esketamine to a certain extent. Finally, C-176, an antagonist of STING, further enhanced the protective effects of esketamine against POCD.
Findings of our study suggest that esketamine can alleviate surgery-induced POCD in rats via inhibition of the STING/TBK1 signaling pathway.