Chen Yuan, Zhou Yi, Cai Jinhan, Xu Jiayi, Hu Chenwei, Chen Huiyue, Hong Yirui, Pan Nanyi, Jiang Yujie, Zhou Chenhui, Wei Hua, Xu Zhipeng, Liu Lin, Wu Xiang, Cui Wei
The First Affiliated Hospital of Ningbo University, Ningbo 315211, China; Translational Medicine Center of Pain, Emotion and Cognition, Zhejiang Provincial Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo 315211, China.
Translational Medicine Center of Pain, Emotion and Cognition, Zhejiang Provincial Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo 315211, China.
Int Immunopharmacol. 2024 Mar 30;130:111772. doi: 10.1016/j.intimp.2024.111772. Epub 2024 Mar 2.
Post-operative cognitive dysfunction (POCD) is a multi-etiological symptom mainly occurred in elderly people after surgery. The activation of retinoic acid receptor α (RARα), a transcriptional factor, was previously predicated to be negatively associated with the occurrence of POCD. However, the mechanisms underlying anti-POCD effects of RARα were still unclear. In this study, AM580, a selective agonist of RARα, and all-trans-retinoic acid (ATRA), a pan agonist of RAR, significantly alleviated cognitive dysfunction and increased the expression of RARα in elderly mice after surgery, which was decreased by RO41-5253, an antagonist of RARα. A bioinformatic study further predicted that the activation of RARα might produce anti-POCD effects via the restoration of synaptic proteins. Both agonists inhibited the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and the phosphorylation of nuclear factorkappa-B (NF-κB), leading to the prevention of microglial over-activation and pro-inflammatory cytokines secretion in the hippocampal regions of elderly mice after surgery. Moreover, AM580 and ATRA increased the expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), and the phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP-response element binding protein (CREB). All these results suggested that the activation of RARα prevented surgery-induced cognitive impairments via the inhibition of neuroinflammation by the reduction of the TLR4/Myd88/NF-κB pathway and the restoration of synaptic proteins by the activation of the BDNF/ERK/CREB pathway, providing a further support that RARα could be developed as a therapeutic target for POCD.
术后认知功能障碍（POCD）是一种多病因症状，主要发生在老年人术后。转录因子视黄酸受体α（RARα）的激活先前被认为与POCD的发生呈负相关。然而，RARα抗POCD作用的潜在机制仍不清楚。在本研究中，RARα的选择性激动剂AM580和RAR的泛激动剂全反式维甲酸（ATRA）显著减轻了老年小鼠术后的认知功能障碍，并增加了RARα的表达，而RARα拮抗剂RO41-5253则降低了RARα的表达。一项生物信息学研究进一步预测，RARα的激活可能通过恢复突触蛋白产生抗POCD作用。两种激动剂均抑制了Toll样受体4（TLR4）、髓样分化因子88（Myd88）的表达以及核因子κB（NF-κB）的磷酸化，从而预防了老年小鼠术后海马区小胶质细胞的过度激活和促炎细胞因子的分泌。此外，AM580和ATRA增加了脑源性神经营养因子（BDNF）和突触后致密蛋白95（PSD95）的表达，以及细胞外信号调节激酶（ERK）和环磷酸腺苷反应元件结合蛋白（CREB）的磷酸化。所有这些结果表明，RARα的激活通过抑制TLR4/Myd88/NF-κB途径的神经炎症和激活BDNF/ERK/CREB途径恢复突触蛋白，预防了手术诱导的认知障碍，为RARα可被开发为POCD的治疗靶点提供了进一步的支持。
