BACKGROUND Postoperative cognitive decline (POCD) is a recognized clinical phenomenon characterized by cognitive impairments in patients following anesthesia and surgery, yet its underlying mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory via activation of TrkB-full length (TrkB-FL) receptors. It has been reported that an abnormal truncation of TrkB mediated by calpain results in dysregulation of BDNF/TrkB signaling and is associated with cognitive impairments in several neurodegenerative disorders. Calpains are Ca2+-dependent proteases, and overactivation of calpain is linked to neuronal death. Since one source of intracellular Ca2+ is N-methyl-d-aspartate receptors (NMDARs) related and the function of NMDARs can be regulated by neuroinflammation, we therefore hypothesized that dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might be involved in the pathogenesis of POCD. METHODS In the present study, 16-month-old C57BL/6 mice were subjected to exploratory laparotomy with isoflurane anesthesia to establish the POCD animal model. For the interventional study, mice were treated with either NMDAR antagonist memantine or calpain inhibitor MDL-28170. Behavioral tests were performed by open field, Y maze, and fear conditioning tests from 5 to 8 days post-surgery. The levels of Iba-1, GFAP, interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), NMDARs, calpain, BDNF, TrkB, bax, bcl-2, caspase-3, and dendritic spine density were determined in the hippocampus. RESULTS Anesthesia and surgery-induced neuroinflammation overactivated NMDARs and then triggered overactivation of calpain, which subsequently led to the truncation of TrkB-FL, BDNF/TrkB signaling dysregulation, dendritic spine loss, and cell apoptosis, contributing to cognitive impairments in aging mice. These abnormities were prevented by memantine or MDL-28170 treatment. CONCLUSION Collectively, our study supports the notion that NMDAR/Ca2+/calpain is mechanistically involved in anesthesia and surgery-induced BDNF/TrkB signaling disruption and cognitive impairments in aging mice, which provides one possible therapeutic target for POCD.

中文翻译：

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NMDAR / Ca2 + /钙蛋白酶介导的BDNF / TrkB信号传导异常可能是衰老小鼠术后认知功能障碍的原因。

背景技术术后认知功能减退（POCD）是一种公认​​的临床现象，其特征在于麻醉和手术后患者的认知障碍，但其潜在机制仍不清楚。脑源性神经营养因子（BDNF）通过激活TrkB全长（TrkB-FL）受体在神经元可塑性，学习和记忆中发挥重要作用。据报道，由钙蛋白酶介导的TrkB的异常截断导致BDNF / TrkB信号传导失调，并且与几种神经退行性疾病的认知障碍有关。钙蛋白酶是Ca 2+依赖性蛋白酶，钙蛋白酶的过度活化与神经元死亡有关。由于细胞内Ca2 +的一种来源与N-甲基-d-天冬氨酸受体（NMDARs）相关，并且NMDARs的功能可以通过神经炎症来调节，因此，我们假设由NMDAR / Ca2 + /钙蛋白酶介导的BDNF / TrkB信号传导失调可能与POCD的发病有关。方法在本研究中，对16个月大的C57BL / 6小鼠进行了异氟烷麻醉的探索性剖腹手术，以建立POCD动物模型。对于干预研究，用NMDAR拮抗剂美金刚或钙蛋白酶抑制剂MDL-28170治疗小鼠。行为测试是在术后5到8天通过开放视野，Y迷宫和恐惧条件测试进行的。Iba-1，GFAP，白介素-1β（IL-1β），IL-6，肿瘤坏死因子-α（TNF-α），NMDAR，钙蛋白酶，BDNF，TrkB，bax，bcl-2，caspase-3的水平，并在海马中确定树突棘密度。结果麻醉和手术引起的神经炎症使NMDARs过度活化，然后触发钙蛋白酶的过度活化，继而导致TrkB-FL，BDNF / TrkB信号失调，树突棘丢失和细胞凋亡被截断，导致衰老小鼠的认知功能障碍。美金刚或MDL-28170治疗可预防这些异常。结论总的来说，我们的研究支持以下观点，即NMDAR / Ca2 + /钙蛋白酶在麻醉和手术诱导的BDNF / TrkB信号传导破坏和认知障碍中机制性参与，这为POCD提供了一种可能的治疗靶点。美金刚或MDL-28170治疗可预防这些异常。结论总的来说，我们的研究支持以下观点，即NMDAR / Ca2 + /钙蛋白酶在麻醉和手术诱导的BDNF / TrkB信号传导破坏和认知障碍中机制性参与，这为POCD提供了一种可能的治疗靶点。美金刚或MDL-28170治疗可预防这些异常。结论总的来说，我们的研究支持以下观点，即NMDAR / Ca2 + /钙蛋白酶在麻醉和手术诱导的BDNF / TrkB信号传导破坏和认知障碍中机制性参与，这为POCD提供了一种可能的治疗靶点。