Chen Ping, Lin Wan-Lan, Liu Xue-Yan, Li Si-Jun, Chen Ruo-Fan, Hu Zhi-Hui, Lin Peng-Tao, Lin Mou-Hui, Shi Meng-Yu, Wu Wei, Wang Ying, Lin Qing-Song, Ye Zu-Cheng
Department of Anesthesiology, Anesthesiology research institute, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China; Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China.
Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China.
Lab Invest. 2025 Feb;105(2):102190. doi: 10.1016/j.labinv.2024.102190. Epub 2024 Nov 22.
Postoperative cognitive dysfunction (POCD) is a common complication with no effective treatment in elderly patients. POCD, Alzheimer disease (AD), and many other cognitive diseases mostly involve neurotoxic microglia response, and recently, β2-microglobulin (B2M) has been suggested to play a pivotal role. A novel pyromeconic acid-styrene hybrid compound D30 was synthesized by our team and shown to be safe and effective in some neurodegenerative mouse models. In this study, we evaluated D30 on POCD and its potential mechanism. Fourteen- to 18-month-old male C57BL/6 mice were used to establish POCD through isoflurane anesthesia and surgery. The plasma of elderly patients was collected pre- and postoperatively. Primary mouse microglia were subjected to various stimulations in multiple experimental designs to imitate in vivo POCD-like conditions. Morris water maze, fear conditioning, western blot, immunofluorescent staining, and blood-brain barrier (BBB) permeability tests were conducted in this study. D30 administration significantly improved learning and memory in aged mice following POCD. Neurotoxic M1 microglia cells were dramatically increased following POCD, manifested as morphologically changing into fewer and shorter branches, enlarged somatic areas, and upregulated expression of iNOS and C1q. Notably, following POCD, B2M was significantly upregulated in the plasma and the brain. D30 treatment significantly suppressed these pathologic changes, by inhibiting the POCD-induced BBB breakdown while suppressing the surge of plasma B2M levels. D30 treatment suppressed POCD-induced surge of B2M and Aβ plaques in the brain and preserved adult hippocampal neurogenesis vulnerable to POCD. Furthermore, postoperative levels of B2M were significantly elevated over the preoperative levels in patients aged 80 years and over. In parallel with mouse plasma after POCD, the postoperative patient plasma was also much more effective at activating M1 microglia. Of note, this POCD plasma-induced activation of M1 microglia was largely prevented by D30 treatment. Taken together, by inhibiting the surge of plasma B2M, protecting BBB integrity, and reducing inflammatory response, D30 protected aged mice from B2M-facilitated POCD.
术后认知功能障碍（POCD）是老年患者常见的并发症，且尚无有效治疗方法。POCD、阿尔茨海默病（AD）以及许多其他认知疾病大多涉及神经毒性小胶质细胞反应，最近，有人提出β2-微球蛋白（B2M）起着关键作用。我们团队合成了一种新型的焦袂康酸-苯乙烯杂化化合物D30，并已证明其在一些神经退行性小鼠模型中是安全有效的。在本研究中，我们评估了D30对POCD及其潜在机制的影响。使用14至18月龄的雄性C57BL/6小鼠通过异氟烷麻醉和手术建立POCD模型。收集老年患者术前和术后的血浆。在多个实验设计中，对原代小鼠小胶质细胞进行各种刺激，以模拟体内类似POCD的情况。本研究进行了莫里斯水迷宫、恐惧条件反射、蛋白质免疫印迹、免疫荧光染色和血脑屏障（BBB）通透性测试。给予D30可显著改善POCD老年小鼠的学习和记忆能力。POCD后神经毒性M1小胶质细胞显著增加，表现为形态上分支变少、变短，体细胞区域增大，以及诱导型一氧化氮合酶（iNOS）和补体C1q的表达上调。值得注意的是，POCD后，血浆和大脑中的B2M显著上调。D30治疗通过抑制POCD诱导的血脑屏障破坏，同时抑制血浆B2M水平的激增，显著抑制了这些病理变化。D30治疗抑制了POCD诱导的大脑中B2M和淀粉样β蛋白（Aβ）斑块的激增，并保留了易受POCD影响的成年海马神经发生。此外，80岁及以上患者术后B2M水平显著高于术前水平。与POCD后的小鼠血浆一样，术后患者血浆在激活M1小胶质细胞方面也更有效。值得注意的是，D30治疗在很大程度上阻止了这种由POCD血浆诱导的M1小胶质细胞激活。综上所述，通过抑制血浆B2M的激增、保护血脑屏障完整性和减少炎症反应，D30保护老年小鼠免受B2M促进的POCD影响。
