Department of Anesthesiology, The third hospital, affiliated to the Xinjiang Medical University, Urumqi, Xinjiang, China.
Department of Second Pulmonary Medicine, The third hospital, affiliated to the Xinjiang Medical University, Urumqi, Xinjiang, China.
Eur J Pharmacol. 2019 Mar 5;846:63-72. doi: 10.1016/j.ejphar.2018.12.034. Epub 2018 Dec 23.
Postoperative cognitive dysfunction (POCD) is commonly seen in patients undergoing major surgeries and may persist. Although neuroinflammation is one of the important contributors to the development of POCD, the mechanisms underlying POCD remain unclear. We performed stabilized tibial fracture operation in male mice. In comparison with sham mice (anesthesia only), the surgery mice exhibited cognitive deficits in a fear conditioning paradigm at postsurgery day 3-7, and increased numbers of microglia and elevated levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) without change of anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. Electrophysiological recordings from CA1 hippocampal neurons revealed that POCD mice exhibited impairment in AMPA receptor-mediated evoked excitatory postsynaptic currents (eEPSCs) without alteration in the rectification property of AMPA receptors. Interestingly, daily intraperitoneal administration of galantamine, an inhibitor of acetylcholinesterase, reversed cognitive dysfunction in surgery mice and attenuated accumulation of microglia and protein levels of IL-1β, IL-6 and TNF-α in the hippocampus. Additionally, galantamine potentiated AMPA receptor-mediated eEPSCs in the hippocampus more prominent in surgery mice than in sham mice. Therefore, enhancement of cholinergic tone in the hippocampus might be a therapeutic strategy for early POCD in terms of suppression of inflammation and normalization of excitatory synaptic transmission.
术后认知功能障碍（POCD）在接受大手术的患者中很常见，并且可能持续存在。虽然神经炎症是导致 POCD 发展的重要因素之一，但 POCD 的发病机制仍不清楚。我们在雄性小鼠中进行了稳定的胫骨骨折手术。与假手术小鼠（仅麻醉）相比，手术小鼠在术后第 3-7 天在恐惧条件反射范式中表现出认知缺陷，并且海马体中的小胶质细胞数量增加，促炎细胞因子（IL-1β、IL-6 和 TNF-α）水平升高，而抗炎细胞因子（IL-4 和 IL-10）没有变化。来自 CA1 海马神经元的电生理记录显示，POCD 小鼠表现出 AMPA 受体介导的诱发兴奋性突触后电流（eEPSCs）的损伤，而 AMPA 受体的整流特性没有改变。有趣的是，乙酰胆碱酯酶抑制剂加兰他敏的每日腹腔内给药可逆转手术小鼠的认知功能障碍，并减轻海马体中小胶质细胞的积累和 IL-1β、IL-6 和 TNF-α的蛋白水平。此外，加兰他敏在手术小鼠中比在假手术小鼠中更明显地增强了海马体中的 AMPA 受体介导的 eEPSCs。因此，增强海马体中的胆碱能张力可能是一种治疗早期 POCD 的策略，可抑制炎症和正常化兴奋性突触传递。
