Postoperative cognitive dysfunction (POCD) is a common phenomenon among elderly patients with unclear etiology. Sterile alpha and TIR motif-containing 1 (Sarm1) plays important roles in neuroinflammation and cognitive function, and activates Calpain which has been shown to promote POCD through TrkB cleavage. This study aims to test the hypothesis that Sarm1 is involved in POCD through regulating Calpain activity. Wild type and Sarm1 knock out mice were exposed to isoflurane. Mouse cognitive function was determined by Morris water maze test. Neuroinflammation was determined by Iba1 and GFAP protein levels and mRNA expression of proinflammatory cytokines. Calpain activation was determined by αII-spectrin degradation and TrkB cleavage. Mitogen-activated protein kinase (MAPK) signaling was determined by c-Jun N-terminal kinase and cJun phosphorylation both in vivo and in vitro by Western blot and immunofluorescence staining. We found that Sarm1 deletion suppressed isoflurane induced cognitive impairment and neuroinflammation. Deletion of Sarm1 inhibited isoflurane induced αII-spectrin degradation and TrkB cleavage, which indicates suppression of Calpain activation. Finally, deletion of Sarm1 suppressed isoflurane induced MAPK signaling both in vivo and in vitro. Our findings suggest that isoflurane anesthesia induced cognitive impairment is prevented by Sarm1 deletion in mice, making Sarm1 a potent therapeutic target for treating or preventing POCD.

术后认知功能障碍（POCD）是病因不明的老年患者的常见现象。含有无菌 α 和 TIR 基序的 1 (Sarm1) 在神经炎症和认知功能中起重要作用，并激活已显示通过 TrkB 切割促进 POCD 的钙蛋白酶。本研究旨在验证 Sarm1 通过调节钙蛋白酶活性参与 POCD 的假设。野生型和 Sarm1 敲除小鼠暴露于异氟醚。小鼠认知功能通过莫里斯水迷宫试验确定。神经炎症由 Iba1 和 GFAP 蛋白水平以及促炎细胞因子的 mRNA 表达决定。通过 αII-spectrin 降解和 TrkB 裂解确定钙蛋白酶活化。通过蛋白质印迹和免疫荧光染色在体内和体外通过 c-Jun N-末端激酶和 cJun 磷酸化确定丝裂原活化蛋白激酶 (MAPK) 信号。我们发现 Sarm1 缺失抑制了异氟醚诱导的认知障碍和神经炎症。Sarm1 的缺失抑制了异氟醚诱导的 αII-Spectrin 降解和 TrkB 裂解，这表明抑制了钙蛋白酶的活化。最后，在体内和体外，Sarm1 的缺失抑制了异氟醚诱导的 MAPK 信号传导。我们的研究结果表明，小鼠 Sarm1 缺失可预防异氟醚麻醉诱导的认知障碍，使 Sarm1 成为治疗或预防 POCD 的有效治疗靶点。我们发现 Sarm1 缺失抑制了异氟醚诱导的认知障碍和神经炎症。Sarm1 的缺失抑制了异氟醚诱导的 αII-Spectrin 降解和 TrkB 裂解，这表明抑制了钙蛋白酶的活化。最后，在体内和体外，Sarm1 的缺失抑制了异氟醚诱导的 MAPK 信号传导。我们的研究结果表明，小鼠 Sarm1 缺失可预防异氟醚麻醉诱导的认知障碍，使 Sarm1 成为治疗或预防 POCD 的有效治疗靶点。我们发现 Sarm1 缺失抑制了异氟醚诱导的认知障碍和神经炎症。Sarm1 的缺失抑制了异氟醚诱导的 αII-Spectrin 降解和 TrkB 裂解，这表明抑制了钙蛋白酶的活化。最后，在体内和体外，Sarm1 的缺失抑制了异氟醚诱导的 MAPK 信号传导。我们的研究结果表明，小鼠 Sarm1 缺失可预防异氟醚麻醉诱导的认知障碍，使 Sarm1 成为治疗或预防 POCD 的有效治疗靶点。