Central cholinergic neuronal degeneration promotes the development of postoperative cognitive dysfunction
Central cholinergic neuronal degeneration promotes the development of postoperative cognitive dysfunction
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中枢胆碱能神经元变性促进术后认知功能障碍的发生
DOI：
10.1038/s41374-018-0174-9
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发表时间：
2019-07-01
影响因子：
5
通讯作者：
Su, Diansan
中科院分区：
文献类型：
--
作者：
Xu, Huan;Chen, Lingke;Su, Diansan
术后认知功能障碍（POCD）一直与发病率和死亡率增加有关。然而，其机制仍然知之甚少。我们假设中枢胆碱能神经元变性促进了POCD的发展。测定麻醉/手术（阑尾切除）对成年和老年小鼠学习记忆及胆碱乙酰转移酶（ChAT）、乙酰胆碱酯酶（AChE）、囊状乙酰胆碱转运蛋白（VAChT）、胆碱转运蛋白（CHT）水平的影响。在老年小鼠中使用乙酰胆碱酯酶抑制剂多奈哌齐或在成年小鼠中使用胆碱能特异性免疫毒素小鼠p75-皂苷（μ -p75-sap）预处理后，对单独的队列进行分析。Morris水迷宫法测定麻醉/手术后大鼠的学习记忆变化。Western blot检测中枢胆碱能系统生物标志物蛋白水平的变化。我们发现麻醉/手术引起的老年小鼠记忆衰退和中枢胆碱能生物标志物（ChAT和VAChT）的衰减，但在成年小鼠中没有。多奈哌齐预处理减少老年小鼠中枢胆碱能损伤，防止麻醉/手术后学习和记忆衰退。相比之下，当用mu-p75-sap预损伤中枢胆碱能神经元时，麻醉/手术后成年小鼠出现认知功能障碍。这些数据表明中枢胆碱能神经元变性促进了POCD的发展。
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.