Wu Wensi, Zhang Xiaojun, Zhou Jiaxin, Yang Hongmei, Chen Junjun, Zhao Le, Zhong Junying, Lin Wei-Jye, Wang Zhi
Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Guangzhou, China.
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Front Pharmacol. 2021 Aug 23;12:738590. doi: 10.3389/fphar.2021.738590. eCollection 2021.
Perioperative neurocognitive disorder (PND) leads to progressive deterioration of cognitive function, especially in aged patients. Demyelination is closely associated with cognitive dysfunction. However, the relationship between PND and demyelination remains unclear. Here we showed that demyelination was related to the pathogenesis of PND. Clemastine, an antihistamine with potency in remyelination, was predicted to have a potential therapeutic effect on PND by next-generation sequencing and bioinformatics in our previous study. In the present study, it was given at 10 mg/kg per day for 2 weeks to evaluate the effects on PND in aged mice. We found that clemastine ameliorated PND and reduced the expression levels of inflammatory factors such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β). Further investigation suggested clemastine increased the expression of oligodendrocyte transcription factor 2 (OLIG2) and myelin basic protein (MBP) to enhance remyelination by inhibiting the overactivation of the WNT/β-catenin pathway. At the same time, the expression of post-synaptic density protein 95 (PSD95, or DLG4), brain-derived neurotrophic factor (BDNF), synaptosomal-associated protein 25 (SNAP25) and neuronal nuclei (NEUN) were also improved. Our results suggested that clemastine might be a therapy for PND caused by anesthetic and surgical factors in aged patients.
围手术期神经认知障碍（PND）会导致认知功能逐渐恶化，在老年患者中尤为明显。脱髓鞘与认知功能障碍密切相关。然而，PND与脱髓鞘之间的关系仍不清楚。在此我们表明，脱髓鞘与PND的发病机制有关。氯马斯汀是一种具有促进髓鞘再生作用的抗组胺药，在我们之前的研究中，通过下一代测序和生物信息学预测其对PND可能具有潜在治疗作用。在本研究中，以每天10mg/kg的剂量给予氯马斯汀，持续2周，以评估其对老年小鼠PND的影响。我们发现氯马斯汀改善了PND，并降低了肿瘤坏死因子α（TNF-α）和白细胞介素-1β（IL-1β）等炎症因子的表达水平。进一步研究表明，氯马斯汀通过抑制WNT/β-连环蛋白通路的过度激活，增加少突胶质细胞转录因子2（OLIG2）和髓鞘碱性蛋白（MBP）的表达，从而增强髓鞘再生。同时，突触后致密蛋白95（PSD95，或DLG4）、脑源性神经营养因子（BDNF）、突触体相关蛋白25（SNAP25）和神经元核抗原（NEUN）的表达也得到改善。我们的结果表明，氯马斯汀可能是治疗老年患者因麻醉和手术因素引起的PND的一种疗法。
