Numerous evidences have highlighted the efficient role of dexmedetomidine (DEX) in multi-organ protection. In the present study, the neuroprotective role of DEX on cerebral ischemic injury and the underlining signaling mechanisms were explored. In order to simulate cerebral ischemic injury, we performed middle cerebral artery occlusion in mice and oxygen-glucose deprivation in neurons. Immunohistochemistry, Western blot analysis, and RT-qPCR were used to examine expression of HDAC5, NPAS4, MDM2, and PSD-95 in hippocampus tissues of MCAO mice and OGD-treated neurons. MCAO mice received treatment with DEX and sh-PSD-95, followed by neurological function evaluation, behavioral test, infarct volume detection by TTC staining, and apoptosis by TUNEL staining. Additionally, gain- and loss-of-function approaches were conducted in OGD-treated neuron after DEX treatment. Cell viability and apoptosis were assessed with the application of CCK-8 and flow cytometry. The interaction between MDM2 and PSD-95 was evaluated using Co-IP assay, followed by ubiquitination of PSD-95 detection. As per the results, HDAC5 and MDM2 were abundantly expressed, while NPAS4 and PSD-95 were poorly expressed in hippocampus tissues of MCAO mice and OGD-treated neurons. DEX elevated viability, and reduced LDH leakage rate and apoptosis rate of OGD-treated neurons, which was reversed following the overexpression of HDAC5. Moreover, HDAC5 augmented MDM2 expression via NPAS4 inhibition. MDM2 induced PSD-95 ubiquitination and degradation. In MCAO mice, DEX improved neurological function and behaviors and decreased infarct volume and apoptosis, which was negated as a result of PSD-95 silencing. DEX plays a neuroprotective role against cerebral ischemic injury by disrupting MDM2-induced PSD-95 ubiquitination and degradation via HDAC5 and NPAS4.

大量证据强调了右美托咪定 (DEX) 在多器官保护中的有效作用。在本研究中，探讨了 DEX 对脑缺血损伤的神经保护作用和重要的信号传导机制。为了模拟脑缺血损伤，我们在小鼠中进行了大脑中动脉闭塞和在神经元中进行氧糖剥夺。免疫组织化学、蛋白质印迹分析和 RT-qPCR 用于检查 HDAC5、NPAS4、MDM2 和 PSD-95 在 MCAO 小鼠和 OGD 处理的神经元的海马组织中的表达。MCAO 小鼠接受 DEX 和 sh-PSD-95 治疗，随后进行神经功能评估、行为测试、TTC 染色检测梗死体积，TUNEL 染色检测细胞凋亡。此外，在 DEX 治疗后，在 OGD 治疗的神经元中进行了功能获得和功能丧失的方法。使用CCK-8和流式细胞术评估细胞活力和细胞凋亡。MDM2 和 PSD-95 之间的相互作用使用 Co-IP 测定进行评估，然后是 PSD-95 检测的泛素化。根据结果​​，HDAC5 和 MDM2 在 MCAO 小鼠的海马组织和 OGD 处理的神经元中大量表达，而 NPAS4 和 PSD-95 表达很少。DEX 提高了 OGD 处理神经元的活力，并降低了 LDH 泄漏率和凋亡率，这在 HDAC5 过表达后逆转。此外，HDAC5 通过抑制 NPAS4 增强了 MDM2 的表达。MDM2 诱导 PSD-95 泛素化和降解。在 MCAO 小鼠中，DEX 改善神经功能和行为，减少梗死体积和细胞凋亡，由于 PSD-95 沉默而被否定。DEX 通过 HDAC5 和 NPAS4 破坏 MDM2 诱导的 PSD-95 泛素化和降解，从而对脑缺血损伤发挥神经保护作用。