Bao Yongjie, Rong Wenni, Zhu An, Chen Yuan, Chen Huiyue, Hong Yirui, Le Jingyang, Wang Qiyao, Naman C Benjamin, Xu Zhipeng, Liu Lin, Cui Wei, Wu Xiang
Department of Anesthesiology, The First Affiliated Hospital of Ningbo University, Ningbo 315010, China.
Translational Medicine Center of Pain, Emotion and Cognition, Ningbo Key Laboratory of Behavioral Neuroscience, Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo 315211, China.
Pharmaceutics. 2023 Sep 13;15(9):2311. doi: 10.3390/pharmaceutics15092311.
Postoperative cognitive dysfunction (POCD) is a clinical syndrome characterizing by cognitive impairments in the elderly after surgery. There is limited effective treatment available or clear pathological mechanisms known for this syndrome. In this study, a Connectivity Map (CMap) bioinformatics model of POCD was established by using differently expressed landmark genes in the serum samples of POCD and non-POCD patients from the only human transcriptome study. The predictability and reliability of this model were further supported by the positive CMap scores of known POCD inducers and the negative CMap scores of anti-POCD drug candidates. Most retinoic acid receptor (RAR) agonists were negatively associated with POCD in this CMap model, suggesting that RAR might be a novel target for POCD. Most importantly, acitretin, a clinically used RAR agonist, significantly inhibited surgery-induced cognitive impairments and prevented the reduction in RARα and RARα-target genes in the hippocampal regions of aged mice. The study denotes a reliable CMap bioinformatics model of POCD for future use and establishes that RAR is a novel therapeutic target for treating this clinical syndrome.
术后认知功能障碍（POCD）是一种临床综合征，其特征为老年人术后出现认知障碍。对于该综合征，有效的治疗方法有限，病理机制也尚不明确。在本研究中，利用唯一一项人类转录组研究中POCD患者和非POCD患者血清样本中的差异表达标志性基因，建立了POCD的连接图谱（CMap）生物信息学模型。已知的POCD诱导剂的阳性CMap评分以及抗POCD候选药物的阴性CMap评分进一步支持了该模型的可预测性和可靠性。在这个CMap模型中，大多数维甲酸受体（RAR）激动剂与POCD呈负相关，这表明RAR可能是POCD的一个新靶点。最重要的是，临床使用的RAR激动剂阿维A显著抑制了手术诱导的认知障碍，并防止了老年小鼠海马区RARα及RARα靶基因的减少。该研究表明了一种可靠的用于未来研究的POCD的CMap生物信息学模型，并确定RAR是治疗这种临床综合征的一个新的治疗靶点。
