围术期利多卡因减轻老年大鼠术后认知功能障碍的机制研究

Post-operative cognitive dysfunction (POCD) is a clinical phenomenon that has drawn significant attention from the public and scientific community. In recent years, there is an increasing concern that general anesthesia/ anesthetics may contribute to POCD because laboratory research has shown that animals exposed to general anesthetics develop learning and memory impairments.But until now, very little is known about how to attenuate volatile anesthetics-induced cognitive impairment. Neuroinflammation can impair cognitive functions. We have shown that isoflurane increases the expression of inducible nitric oxide synthase, a protein that contributes to inflammatory response, in rat brains. Isoflurane has been shown to increase activated caspase 3, a key enzyme to lead to cell apoptosis, in mouse brains. Neuroinflammation, Aβ accumulation, neurodegeneration and hyperphosphorylated tau accumulation are key pathological features of AD brains. Our previous studies in USA showed that isoflurane can lead to adult and old rats neuronal apoptosis, and result in postoperative cognitive dysfunction. Our previous studies also found that lidocaine can reduce isoflurane-induced cognitive dysfunction in old rats. However, its mechanism is unclear. Thus, we hypothesize that isoflurane induces cognitive impairment and AD-like neuropathology and that lidocaine attenuates these changes possibly via inhibition of neuroinflammation in aged animals. Our project will study the effects of lidocaine on Aβ accumulation, neutoinflammation and neuronal apoptosis. Based on these resluts, we will try to explain the mechanisms of lidocaine neuroprotection in isoflurane- induced cognitive dysfunction.

老年患者术后认知功能障碍是目前麻醉学研究热点，但目前尚未有有效防治方法。研究表明吸入麻醉药物可能参与诱导术后认知功能障碍。本人在美国前期研究一方面证实异氟醚吸入可导致成年及老年大鼠神经元凋亡、认知功能障碍，可能与异氟醚吸入引起皮质及海马区β淀粉蛋白积聚，继而引发该区域炎症反应、加重线粒体损伤有关；另一方面，更令人兴奋的是：还观察到利多卡因可减轻异氟醚导致的老年大鼠认知功能障碍，但机制尚不明确，我们推测可能通过抑制大脑炎症反应、减轻线粒体损伤、减少神经元凋亡而达到上述保护效应。本研究将①进一步观察利多卡因对异氟醚处理后老年大鼠皮质及海马区β淀粉蛋白、炎症反应因子、神经元等的影响；②在此基础上探究利多卡因对异氟醚处理后老年大鼠认知功能障碍的神经保护机制；为临床应用利多卡因防治术后认知功能障碍提供理论依据。

近年来研究表明，异氟醚能够引起凋亡，从而导致A β蛋白的聚集，最终引起术后认知功能障碍。在前期的研究中，我们发现利多卡因能够减轻老年大鼠异氟醚引起的认知功能障碍，并且减少活化的casepase-3的产生。其利多卡因这种保护作用的具体机制尚不清楚。由于casepase-3 是凋亡的关键酶，并且有报道指出异氟醚能够引起线粒体功能紊乱引起凋亡，所以我们在该实验中假设利多卡因是通过减少异氟醚引起的凋亡和线粒体紊乱，从而减轻异氟醚引起的认知功能障碍。我们选取了H4神经胶质细胞和Fisher 344 老年大鼠的海马组织作为实验对象，对其予以异氟醚及利多卡因处理，检测细胞凋亡，电镜观察细胞组织线粒体形态，JC-1检测线粒体膜电位变化及线粒体呼吸链复合酶活性的检测。结果表明，无论是在神经胶质细胞中，还是海马组织中，利多卡因都能减少异氟醚引起的凋亡，减轻异氟醚对线粒体的损害，逆转异氟醚引起的线粒体的膜电位及线粒体呼吸链复合酶活性的变化。这些结果证实利多卡因通过减少异氟醚引起的凋亡和线粒体紊乱，从而减轻异氟醚引起的认知功能障碍。这些结果在一定程度上为临床上提供更安全的吸入麻醉，减少术后认知障碍提供了新的理论依据。