Department of Anesthesiology, Seventh People's Hospital of Shanghai University of TCM, Shanghai, China.
Department of Anesthesiology, Longhua Hospital Shanghai University of TCM, Shanghai, China.
Eur J Neurosci. 2022 Aug;56(4):4317-4332. doi: 10.1111/ejn.15751. Epub 2022 Jul 16.
Postoperative cognitive dysfunction (POCD) is a prevalent disorder after anaesthesia in the elderly patients. Roflumilast (RF), a phosphodiesterase 4 (PDE-4) inhibitor, could improve cognition with no side effects. Here, we sought to explore the efficacy of RF in the improvement of cognitive dysfunction caused by sevoflurane (Sev). Sprague-Dawley rats were anaesthetized, and the hippocampal neurons were treated with Sev to develop in vivo and in vitro POCD models, followed by RF administration. The mechanism of the PKA-CREB and MEK/ERK pathways in the pathogenesis of POCD was explored. Sev impaired the cognitive functions of rats, significantly reduced cyclic adenosine monophosphate (cAMP) concentrations and blocked the PKA-CREB and MEK/ERK pathways. Moreover, the Sev-treated rats and neurons exhibited enhanced apoptosis and reactive oxygen species (ROS). After treatment with RF, rats had better learning and memory function, and the activity of neurons in hippocampus and cortex was improved. Loss-of-function assay indicated that PKA-CREB and MEK/ERK signalling impairment reduced cAMP levels and promoted apoptosis and ROS in rat hippocampus and neurons. Generally, RF promotes neuronal activity in rats after Sev treatment by maintaining cAMP levels and sustaining the activation of PKA-CREB and MEK/ERK pathways. This might offer novel sights for POCD therapy.
术后认知功能障碍（POCD）是老年患者麻醉后常见的疾病。罗氟司特（RF），一种磷酸二酯酶 4（PDE-4）抑制剂，可改善认知功能而无副作用。在这里，我们试图探讨 RF 对七氟醚（Sev）引起的认知功能障碍的疗效。用 Sev 麻醉 Sprague-Dawley 大鼠，并对海马神经元进行处理，以建立体内和体外 POCD 模型，然后给予 RF 治疗。探讨了 PKA-CREB 和 MEK/ERK 通路在 POCD 发病机制中的作用。 Sev 损害了大鼠的认知功能，显著降低了环磷酸腺苷（cAMP）浓度，并阻断了 PKA-CREB 和 MEK/ERK 通路。此外，Sev 处理的大鼠和神经元表现出增强的细胞凋亡和活性氧（ROS）。用 RF 治疗后，大鼠的学习和记忆功能更好，海马和皮质神经元的活性得到改善。功能丧失实验表明，PKA-CREB 和 MEK/ERK 信号通路的损害降低了 cAMP 水平，并促进了大鼠海马和神经元的细胞凋亡和 ROS 的产生。总的来说，RF 通过维持 cAMP 水平和维持 PKA-CREB 和 MEK/ERK 通路的激活，促进 Sev 处理后大鼠神经元的活性。这可能为 POCD 的治疗提供新的思路。
