右美托咪定术中干预对老年小鼠围术期神经认知障碍的影响及其可能机制

Effect of intraoperative dexmedetomidine intervention on perioperative neurocognitive disorders in aged mice

目的:探讨术中右美托咪定(dexmedetomidine,DEX)干预对老年小鼠围术期神经认知障碍(perioperative neurocognitive disorders,PND)的影响及其具体机制。方法:在C57BL/6J老年小鼠行左肝外叶切除术以建立PND小鼠模型,应用Morris水迷宫及Y迷宫实验评价术中DEX干预对老年小鼠术后认知行为的影响;应用尼氏染色和TUNEL染色观察老年小鼠术后海马CA1区神经元变化情况;应用膜片钳技术记录术中DEX干预对老年小鼠术后海马CA1区长时程增强的影响;应用免疫荧光和免疫组化染色检测术中DEX干预对老年小鼠术后海马星形胶质细胞活化的影响;应用Western blot检测术中DEX干预对老年小鼠术后海马肿瘤坏死因子α(tumor necrosis factor-α,TNF-α)、白细胞介素6(interleukin-6,IL-6)及cleaved caspase-3蛋白水平的影响。结果:术中DEX干预可显著改善老年小鼠术后认知功能(P<0.01)。术中DEX干预可显著抑制手术导致的老年小鼠海马神经元丢失(P<0.01),并可显著逆转手术引起的场兴奋性突触后电位幅度减小,显著降低手术导致的老年小鼠海马TNF-α、IL-6和cleaved caspase-3水平升高(P<0.01)。结论:术中DEX干预可通过抑制海马星形胶质细胞活化、减轻神经炎症及神经元凋亡而保护海马神经元,达到改善老年小鼠术后认知功能的作用。

AIM:To investigate the effect of dexmedetomidine(DEX)on perioperative neurocognitive disorders(PND)in aged mice and its mechanism.METHODS:The PND animal model was established by hepatic left lateral lobectomy in C57 BL/6 J aged mice,and the effects of intraoperative DEX intervention on postoperative cognitive behavior in aged mice were evaluated by Morris water maze and Y maze experiments.The effects of intraoperative DEX intervention on the changes of neurons in hippocampal CA1 region of aged mice were observed by Nissl staining and TUNEL staining.The effect of intraoperative DEX intervention on long-term potentiation in hippocampal CA1 region was recorded by patchclamp technique.The effects of intraoperative DEX intervention on hippocampal astrocyte activation in aged mice were detected by immunofluorescence and immunohistochemistry.The effects of intraoperative DEX intervention on the protein levels of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and cleaved caspase-3 in hippocampal CA1 region of aged mice were determined by Western blot.RESULTS:Intraoperative DEX intervention attenuated postoperative cognitive dysfunction in aged mice(P<0.01).Intraoperative DEX intervention significantly inhibited surgery-induced hippocampal neuron loss(P<0.01),reversed surgery-induced decrease in field excitatory postsynaptic potential amplitude,and reduced surgery-induced increases in the protein levels of TNF-α,IL-6 and cleaved caspase-3 in hippocampal CA1 region of aged mice(P<0.01).CONCLUSION:Dexmedetomidine protects hippocampal neurons and improves postoperative cognitive function in aged mice by inhibiting hippocampal astrocyte activation and reducing neuronal inflammation and neuronal apoptosis.