背景:术后认知功能障碍(POCD)是老年人麻醉和手术的常见神经系统并发症。神经炎症已被确定为POCD的标志。然而,目前仍缺乏安全有效的POCD治疗方法。衣康酸酯是源自三羧酸循环的免疫调节代谢物,通过激活核因子类红细胞2相关因子2(Nrf2)途径发挥抗炎作用。在这项研究中,我们研究了4-辛基衣康酸(OI)的作用和潜在的机制,一种可渗透细胞的衣康酸酯衍生物,老年小鼠POCD的研究。
方法:对18月龄雄性C57BL/6小鼠在异氟烷麻醉下进行无菌剖腹手术,同时保持自主通气,建立POCD动物模型。手术后将OI腹膜内注射到小鼠体内。分离原代小胶质细胞和神经元,并用脂多糖(LPS)处理,异氟烷,还有OI.认知功能,神经炎症反应,以及肠道微生物群及其代谢物的水平进行了评估。为了确定OI在POCD中的治疗作用的潜在机制,腹膜内施用Nrf2的拮抗剂ML385。认知功能,神经炎症反应,内源性神经发生,神经元凋亡,并对Nrf2/细胞外信号相关激酶(ERK)信号通路进行评价。
结果:我们的发现表明,OI治疗可显着减轻麻醉/手术引起的认知障碍,伴随着神经炎症细胞因子IL-1β和IL-6的水平降低,以及海马中小胶质细胞和星形胶质细胞的活化受到抑制。同样,OI处理在体外抑制LPS和异氟烷诱导的原代小胶质细胞中IL-1β和IL-6的表达。腹膜内施用OI导致肠道微生物群的改变,并促进与神经发生相关的微生物群衍生的代谢物的产生。我们进一步证实,OI促进了衰老小鼠海马齿状回的内源性神经发生并抑制了神经元凋亡。机械上,我们在体外和体内观察到海马神经元中Nrf2表达的减少,这种情况被OI治疗逆转了。我们发现OI治疗需要Nrf2来抑制POCD中的神经炎症。OI暴露引起的POCD恢复和神经发生的增强,至少部分地,Nrf2/ERK信号通路的激活。
结论:我们的研究结果表明,OI可以通过稳定肠道菌群和激活Nrf2信号来抑制神经炎症和促进神经发生,从而减轻麻醉/手术引起的认知障碍。增强内源性衣康酸或补充外源性衣康酸衍生物可能代表治疗POCD的新策略。
BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice.
METHODS: A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated.
RESULTS: Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1β and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1β and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway.
CONCLUSIONS: Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.