Li Chenglong, Cong Yushuang, Song Wanying, Wu Yujin, Gou Xi, Qi Sihua
Department of Anesthesiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, China.
Department of Anesthesiology, The First Bethune Hospital of Jilin University, Changchun, Jilin, 130031, China.
J Neuroimmune Pharmacol. 2025 Apr 11;20(1):34. doi: 10.1007/s11481-025-10201-w.
Cognitive impairment following surgical procedures, termed postoperative cognitive dysfunction (POCD), is a significant complication affecting the central nervous system. This condition stems from the combined impacts of anesthesia and surgical intervention, with microglial-induced neuroinflammation identified as the primary pathological mechanism. Irisin, a recently identified hormone released during physical exercise, has shown remarkable anti-inflammatory and neuroprotective properties, largely through its ability to modulate microglial activation in various central nervous system disorders. In this study, we explored the protective effects of irisin and its underlying mechanisms in a mouse model of POCD and BV2 microglial cells. Our results demonstrated that irisin effectively mitigated hippocampal-dependent cognitive deficits in mice subjected to exploratory laparotomy. Additionally, irisin facilitated the phenotypic shift of microglia from the pro-inflammatory M1 state to the anti-inflammatory and reparative M2 state. Furthermore, irisin upregulated the expression of Sirt3 in the postoperative hippocampus of mice. Importantly, pharmacological inhibition of Sirt3 activity using 3-TYP nullified the neuroprotective effects of irisin. In vitro studies revealed that irisin increased the expression of Sirt3 and autophagy-related proteins in lipopolysaccharide-activated BV2 microglial cells. Notably, Sirt3 knockout impeded irisin-induced autophagy enhancement and inhibited the polarization of microglia toward the M2 phenotype. Collectively, these findings highlight irisin's ability to attenuate POCD by driving the phenotypic transition of microglia from M1 to M2 through a mechanism involving Sirt3-mediated autophagy. This novel pathway underscores the therapeutic potential of irisin as a promising candidate for managing POCD.
外科手术后的认知障碍，称为术后认知功能障碍（POCD），是一种影响中枢神经系统的重大并发症。这种情况源于麻醉和手术干预的综合影响，其中小胶质细胞诱导的神经炎症被确定为主要病理机制。鸢尾素是最近在体育锻炼过程中发现的一种激素，已显示出显著的抗炎和神经保护特性，主要是通过其调节各种中枢神经系统疾病中小胶质细胞激活的能力。在本研究中，我们在POCD小鼠模型和BV2小胶质细胞中探讨了鸢尾素的保护作用及其潜在机制。我们的结果表明，鸢尾素有效减轻了接受剖腹探查术的小鼠海马依赖性认知缺陷。此外，鸢尾素促进了小胶质细胞从促炎M1状态向抗炎和修复性M2状态的表型转变。此外，鸢尾素上调了小鼠术后海马中Sirt3的表达。重要的是，使用3-TYP对Sirt3活性进行药理学抑制消除了鸢尾素的神经保护作用。体外研究表明，鸢尾素增加了脂多糖激活的BV2小胶质细胞中Sirt3和自噬相关蛋白的表达。值得注意的是，Sirt3基因敲除阻碍了鸢尾素诱导的自噬增强，并抑制了小胶质细胞向M2表型的极化。总体而言，这些发现突出了鸢尾素通过涉及Sirt3介导的自噬机制驱动小胶质细胞从M1向M2表型转变来减轻POCD的能力。这一新途径强调了鸢尾素作为治疗POCD的有前景候选药物的治疗潜力。
