Department of Anesthesiology, Shishi General Hospital, Fujian Province, China.
Department of Anesthesiology, Zhuzhou Central Hospital, Hunan Province, China.
Exp Neurol. 2024 Feb;372:114646. doi: 10.1016/j.expneurol.2023.114646. Epub 2023 Dec 7.
Esketamine, the S(+) enantiomer of ketamine, exhibits good anesthetic efficacy and controllability; however, its potential clinical applications, particularly in sepsis-associated encephalopathy (SAE), remain underexplored. SAE involves the development of diffuse brain dysfunction after sepsis, leading to markedly increased sepsis-related disability and mortality. In this study, we investigated the effects of esketamine pretreatment on acute SAE.
Mice were randomly divided into four groups: control (C, n = 22), acute SAE (L, n = 22), esketamine pretreatment + acute SAE (EL, n = 22), and nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor (ML385) + esketamine pretreatment + acute SAE (N + EL, n = 22). Acute SAE was established using intraperitoneal (i.p.) injection of lipopolysaccharide (LPS; 10 mg/kg), while controls received equal amounts of saline. The EL group received daily i.p. injections of esketamine (10 mg/kg) for 5 consecutive days, followed by LPS on day 6. The N + EL group received i.p. injections of ML385 (30 mg/kg) 1 h before esketamine pretreatment. The remainder of treatment followed the same protocol as the EL group. Behavioral tests were performed 24 h post-LPS injection, and whole blood and brain tissues were collected for further analysis.
Esketamine improved sepsis symptoms, 7-day survival, and spatial cognitive impairment, without altering locomotor activity. Moreover, esketamine reversed the LPS-induced increase in serum S100 calcium-binding protein β and neuron-specific enolase levels and reduced hippocampal neuroinflammation, oxidative stress, and neuronal apoptosis in the EL group. However, these neuroprotective effects of esketamine were reversed by ML385.
The results of our study suggest that esketamine pretreatment mitigates acute SAE, highlighting the involvement of the Nrf2/heme oxygenase-1 pathway in mediating its neuroprotective effects.
氯胺酮的 S(+)对映异构体右美沙酮具有良好的麻醉效果和可控性；然而，其潜在的临床应用，特别是在脓毒症相关脑病（SAE）中的应用，仍未得到充分探索。SAE 涉及到脓毒症后弥漫性脑功能障碍的发展，导致明显增加了与脓毒症相关的残疾和死亡率。在这项研究中，我们研究了右美沙酮预处理对急性 SAE 的影响。
小鼠随机分为四组：对照组（C 组，n=22）、急性 SAE 组（L 组，n=22）、右美沙酮预处理+急性 SAE 组（EL 组，n=22）和核因子红细胞 2 相关因子 2（Nrf2）抑制剂（ML385）+右美沙酮预处理+急性 SAE 组（N+EL 组，n=22）。急性 SAE 采用腹腔（i.p.）注射脂多糖（LPS；10mg/kg）建立，对照组给予等量生理盐水。EL 组每天腹腔注射右美沙酮（10mg/kg）连续 5 天，第 6 天给予 LPS。N+EL 组在右美沙酮预处理前 1 小时腹腔注射 ML385（30mg/kg）。其余治疗方案与 EL 组相同。LPS 注射后 24 小时进行行为测试，并采集全血和脑组织进行进一步分析。
右美沙酮改善了脓毒症症状、7 天存活率和空间认知障碍，而不改变运动活动。此外，右美沙酮逆转了 LPS 诱导的血清 S100 钙结合蛋白 β 和神经元特异性烯醇化酶水平的升高，并减少了 EL 组海马神经炎症、氧化应激和神经元凋亡。然而，ML385 逆转了右美沙酮的这些神经保护作用。
本研究结果表明，右美沙酮预处理减轻了急性 SAE，提示 Nrf2/血红素加氧酶-1 通路参与介导其神经保护作用。
