低氧环境下丙泊酚致未成熟脑认知功能障碍的分子机制

With increasing in the number of general anesthesia, the incidence of POCD(postoperative cognitive dysfunction) increased markedly, up to 50%.We previously reported that propofol in combination with hypoxia lastingly impair cognitive function in newborn rats and induced apoptosis, reduced neuronal loss. However, the mechanism remains unknown.As known, inhaled anesthetics desflurane in combination with the hypoxia led to neurotoxicity and cognitive dysfunction by Aβ pathway. Therefore, we speculate that propofol in combination with hypoxia induced nerve dysfunction through P13-K , PKB and MAPK signal pathway and GSK-3α and GSK-3? , resulting in the increase of cellular A? and Tau protein phosphorylation, resulting in further oxidative stress , intracellular calcium homeostasis imbalance, leading to apoptosis and cognitive impairment . Based on previous findings, the current study aims to further investigate the molecular mechanism by which repeated propofol anesthesia induced cognitive dysfunction in infant rats under hypoxic conditions, confirm the involvement of Aβ pathway in cognitive impairment. Moreover, we will try to explore P13-K、PKB and MAPK signal pathway contribute to the increase of cellular A? and Tau protein phosphorylation. The performance of current program may be helpful to effectively intervention the complications of anesthesia in clinic, and provide new therapeutic strategies for POCD.

随着全身麻醉数量的增加，术后认知功能障碍（POCD）与日俱增，发生率高达50％。我们前期研究证实：低氧环境下丙泊酚麻醉引起新生大鼠长时间学习、记忆功能下降、海马神经细胞明显凋亡、数量减少,但作用机制尚未阐明。研究已证实吸入麻醉药地氟醚合并低氧是通过Aβ途径产生神经毒性，引起认知功能障碍。由此推测丙泊酚合并低氧引起长时间神经功能损伤是否经过P13-K、PKB及MAPK途径，受GSK-3α及GSK-3?调节，引起细胞A?的增加和Tau蛋白磷酸化，进一步产生氧化应激、细胞内钙稳态失调，从而导致细胞凋亡及认知障碍的发生。本项目拟在前期研究基础上，深入研究低氧环境下丙泊酚麻醉引起学习、记忆功能下降的机制，阐明A?途径介导认知障碍的分子机制，证实P13-K、PKB及MAPK信号途径参与A?的生成和Tau蛋白磷酸化。本项目的实施有助于有效干预麻醉手术后并发症的发生，有望为POCD的治疗提供新的思路。

随着全身麻醉数量的增加，术后认知功能障碍（POCD）与日俱增，发生率高达50％。我们前期研究证实：低氧环境下丙泊酚麻醉引起新生大鼠长时间学习、记忆功能下降、海马神经细胞明显凋亡、数量减少,但作用机制尚未阐明。研究已证实吸入麻醉药地氟醚合并低氧是通过Aβ途径产生神经毒性，引起认知功能障碍。由此推测丙泊酚合并低氧引起长时间神经功能损伤是否经过P13-K、PKB及MAPK途径，受GSK-3α及GSK-3ß调节，引起细胞Aß的增加和Tau蛋白磷酸化，进一步产生氧化应激、细胞内钙稳态失调，从而导致细胞凋亡及认知障碍的发生。本项目拟在前期研究基础上，深入研究低氧环境下丙泊酚麻醉引起学习、记忆功能下降的机制，阐明Aß途径介导认知障碍的分子机制，证实P13-K、PKB及MAPK信号途径参与Aß的生成和Tau蛋白磷酸化。本项目的实施有助于有效干预麻醉手术后并发症的发生，有望为POCD的治疗提供新的思路