CCK-8对甲基苯丙胺诱导神经炎症反应的影响及其信号调控机制研究

Methamphetamine (MA) is the most serious abused drug all over the world, and can elicit serious damage in central nerve system. Activation of microglia and CNS inflammation induced by microglia played an important role in MA triggered nerve injury. Cholecystokinin octapeptide (CCK-8) is a typical neuropeptide and can regulate the process of pain, drug abuse and central ischemic injury. Our previous studies found that CCK-8 could regulate the activity of various peripheral immune cells, and exert anti-inflammatory effects on the body. However, no report focuses on whether CCK-8 could develop a protective function in MA induced nerve injury by inhibiting the activation of microglia and the CNS inflammation. The present study aims to investigate the effects of CCK-8 on resting state microglia and MA activated microglia, as well as to observe the dose-effect relationship of CCK-8 and receptor mechanism. Furthermore, we will explore the effects of MA and CCK-8 on IKK/PKA-IkB-NF-kB signal pathway and the interaction of co-activator p300/CBP and NF-kB in microglia, in order to clear the protective effect of CCK-8 on MA induced inflammation and the signal regulation mechanism. We're looking forward to find a new target in the medical treatment of MA abuse.

甲基苯丙胺(MA)是目前全球泛滥最严重的一种新型毒品，对中枢神经系统可造成严重损伤。小胶质细胞活化及其诱发的中枢炎症反应在MA神经损伤过程中发挥着重要作用。八肽胆囊收缩素 (CCK-8) 是一种典型的神经肽，参与痛觉、药物成瘾、中枢缺血性损伤等过程。我们以往研究发现CCK-8还可调节外周多种免疫细胞活性，发挥抗炎作用。但是CCK-8是否可通过抑制MA诱导的小胶质细胞活化及中枢炎症反应，对MA神经损伤发挥保护作用,未见相关报道。本研究将从体内和体外水平系统考察CCK-8对静息或MA激活的小胶质细胞具有何种调节作用，明确其抗炎的量效关系和受体机制；并观察MA和CCK-8对小胶质细胞IKK/PKA-IkB-NF-kB信号通路以及辅转录因子p300/CBP与NF-kB相互作用的影响，以阐明CCK-8对MA炎症性损伤的保护作用及其信号调控机制，期待为 MA滥用防治提供新的药物干预靶标。

甲基苯丙胺是目前全球泛滥最严重的一种新型毒品，对中枢神经系统可造成严重损伤。氧化应激、小胶质细胞活化及其诱发的中枢炎症反应在甲基苯丙胺神经损伤过程中发挥着重要作用。八肽胆囊收缩素（CCK-8）是一种典型的神经肽，参与痛觉、药物成瘾、中枢缺血性损伤等过程。本项目系统考察了CCK-8对甲基苯丙胺诱导的氧化应激反应、小胶质细胞活化和中枢炎症反应的影响及其机制，发现CCK-8可剂量依赖性地抑制甲基苯丙胺诱导小胶质细胞活化及炎症因子的产生，抑制甲基苯丙胺诱导的PC12细胞氧化应激反应；提示CCK-8可通过抗炎、抗氧化应激机制对甲基苯丙胺神经损伤发挥保护作用。另外，本项目阐明了CCK-8可通过激活CCK2受体调节PKA／PKC信号抑制细胞内核转录因子NF-kB活性发挥抗炎作用；通过抑制CCK2受体ROS及Nox复合物的形成减少甲基苯丙胺诱导的氧化应激反应。上述结果为CCK-8 在甲基苯丙胺滥用防治方面的实际应用提供了新的思路和可靠的理论依据。