Department of Anesthesiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China.
Department of Anesthesiology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, 200433, China.
Lab Invest. 2019 Jul;99(7):1078-1088. doi: 10.1038/s41374-018-0174-9. Epub 2019 Jan 9.
Postoperative cognitive dysfunction (POCD) is consistently associated with increased morbidity and mortality. However, its mechanism remains poorly understood. We hypothesized that central cholinergic neuronal degeneration facilitates the development of POCD. The impact of anesthesia/surgery (appendectomy) on learning and memory and the levels of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), vesicular acetylcholine transporter (VAChT), and choline transporter (CHT) in adult and aged mice were measured. Separate cohorts were analyzed after pretreatment with donepezil, an AChE inhibitor, in aged mice or with murine-p75-saporin (mu-p75-sap), a cholinergic-specific immunotoxin, in adult mice. Morris Water Maze was used to measure the learning and memory changes after anesthesia/surgery. Western blot was used to measure the changes in the protein levels of the biomarkers of the central cholinergic system. We found that anesthesia/surgery-induced memory decline and attenuation of central cholinergic biomarkers (ChAT and VAChT) in aged mice but not in adult mice. Donepezil pretreatment reduced central cholinergic impairment in the aged mice and prevented learning and memory declines after anesthesia/surgery. In contrast, when central cholinergic neurons were pre-injured with mu-p75-sap, cognitive dysfunction developed in the adult mice after anesthesia/surgery. These data suggest that central cholinergic neuronal degeneration facilitates the development of POCD.
术后认知功能障碍（POCD）与发病率和死亡率的增加密切相关。然而，其发病机制仍不清楚。我们假设中枢胆碱能神经元变性促进了 POCD 的发展。测量了麻醉/手术（阑尾切除术）对成年和老年小鼠学习和记忆的影响，以及乙酰胆碱转移酶（ChAT）、乙酰胆碱酯酶（AChE）、囊泡乙酰胆碱转运体（VAChT）和胆碱转运体（CHT）的水平。在老年小鼠中用 AChE 抑制剂多奈哌齐预处理或在成年小鼠中用胆碱能特异性免疫毒素鼠 p75-saporin（mu-p75-sap）预处理后，对不同队列进行了分析。Morris 水迷宫用于测量麻醉/手术后学习和记忆的变化。Western blot 用于测量中枢胆碱能系统生物标志物的蛋白水平变化。我们发现麻醉/手术引起老年小鼠记忆减退和中枢胆碱能生物标志物（ChAT 和 VAChT）减弱，但在成年小鼠中没有。多奈哌齐预处理减轻了老年小鼠的中枢胆碱能损伤，并防止了麻醉/手术后的学习和记忆下降。相反，当用 mu-p75-sap 预先损伤中枢胆碱能神经元时，成年小鼠在麻醉/手术后会出现认知功能障碍。这些数据表明中枢胆碱能神经元变性促进了 POCD 的发展。
