Background: Postoperative cognitive dysfunction (POCD) is a common clinical complication in elderly patients, but its underlying mechanism remains unclear. Receptor-interacting protein kinase 1 (RIPK1), a key molecule mediating necroptosis and regulated by transforming growth factor β-activated kinase 1 (TAK1), was reported to be associated with cognitive impairment in several neurodegenerative diseases. This study was conducted to investigate the possible role of TAK1/RIPK1 signalling in POCD development following surgery in rats. Methods: Young (2-month-old) and old (24-month-old) Sprague–Dawley rats were subjected to splenectomy under isoflurane anaesthesia. The young rats were treated with the TAK1 inhibitor takinib or the RIPK1 inhibitor necrostatin-1 (Nec-1) before surgery, and old rats received adeno-associated virus (AAV)-TAK1 before surgery. The open field test and contextual fear conditioning test were conducted on postoperative day 3. The changes in TNF-α, pro-IL-1β, AP-1, NF-κB p65, pRIPK1, pTAK1 and TAK1 expression and astrocyte and microglia activation in the hippocampus were assessed. Results: Old rats had low TAK1 expression and were more susceptible to surgery-induced POCD and neuroinflammation than young rats. TAK1 inhibition exacerbated surgery-induced pRIPK1 expression, neuroinflammation and cognitive dysfunction in young rats, and this effect was reversed by a RIPK1 inhibitor. Conversely, genetic TAK1 overexpression attenuated surgery-induced pRIPK1 expression, neuroinflammation and cognitive dysfunction in old rats. Conclusion: Ageing-related decreases in TAK1 expression may contribute to surgery-induced RIPK1 overactivation, resulting in neuroinflammation and cognitive impairment in old rats.

背景：术后认知功能障碍（POCD）是老年患者常见的临床并发症，但其潜在机制尚不清楚。受体相互作用蛋白激酶 1 (RIPK1) 是介导坏死性凋亡的关键分子，受转化生长因子 β 激活激酶 1 (TAK1) 调节，据报道与多种神经退行性疾病中的认知障碍有关。本研究旨在探讨 TAK1/RIPK1 信号在大鼠手术后 POCD 发展中的可能作用。方法：在异氟烷麻醉下对年轻（2 个月大）和老年（24 个月大）Sprague-Dawley 大鼠进行脾切除术。年轻大鼠术前接受TAK1抑制剂塔吉尼或RIPK1抑制剂necrostatin-1（Nec-1）治疗，老年大鼠术前接受腺相关病毒（AAV）-TAK1治疗。术后第3天进行旷场测试和情景恐惧条件反射测试。观察大鼠中TNF-α、pro-IL-1β、AP-1、NF-κB p65、pRIPK1、pTAK1和TAK1表达以及星形胶质细胞和小胶质细胞激活的变化。对海马体进行了评估。结果：老年大鼠TAK1表达低，比年轻大鼠更容易受到手术引起的POCD和神经炎症的影响。TAK1 抑制加剧了年轻大鼠手术诱导的 pRIPK1 表达、神经炎症和认知功能障碍，而这种效应可以被 RIPK1 抑制剂逆转。相反，基因 TAK1 过表达减弱了老年大鼠手术诱导的 pRIPK1 表达、神经炎症和认知功能障碍。结论：年龄相关的 TAK1 表达下降可能导致手术引起的 RIPK1 过度激活，导致老年大鼠神经炎症和认知障碍。