黄芩苷调控Nrf2/ARE信号通路影响ADHD模型DA递质转运平衡机制研究

ADHD严重危害儿童身心健康，探索其发病机制及有效治疗措施具有重要意义。申请人前期研究发现黄芩苷能够控制ADHD核心症状，深入研究表明，黄芩苷可以上调VMAT2及Nrf2/ARE信号通路中Nrf2蛋白表达和ATP、PKA酶活性影响脑内DA水平。据此我们提出假说：黄芩苷能够激活Nrf2/ARE信号通路启动ARE依赖型内源性抗氧化酶表达，抑制ROS蓄积导致的细胞因子活化，产生抗氧化应激效应，进而抑制DAT-VMAT2转入-转出失衡以维持脑内DA水平。本课题以SHR大鼠为模型，采用VMAT2特异性阻断剂，运用微透析技术、代谢组学技术、激光共聚焦技术等检测SHR大鼠脑脊液及前额叶、纹状体内Nrf2、ARE、DAT、DA、VMAT2及ROS等的变化，以阐明黄芩苷调控Nrf2/ARE信号通路发挥抗氧化应激效应影响DA递质转运平衡治疗ADHD分子机制，为明确黄芩苷治疗ADHD作用机制及推广应用提供依据。

Attention deficit hyperactivity disorder (ADHD) seriously damages children's physical and mental health, it is of great significance to explore its pathogenesis and effective treatment measures. Our previous studies have found that baicalin can control the core symptoms of ADHD. Further studies indicated that baicalin can up-regulate the VMAT2 and Nrf2 expression, and the activities of ATP and PKA enzymes in the Nrf2/ARE signaling pathways to affect DA levels in the brain. Therefore, we propose the hypothesis that baicalin can activate the Nrf2/ARE signaling pathway to initiate the expression of ARE dependent endogenous antioxidant enzymes, and inhibit the activation of cytokines caused by ROS accumulation, and play the anti-oxidative stress effects to inhibit transferring imbalance of DAT-VMAT2 to maintain DA levels in the brain. In this study, SHR rat would be selected as ADHD animal model and VMAT2 specific blocker would be applied. Microdialysis in vivo cerebrospinal fluid collection technology, metabolomics technology, and laser confocal technology would be used to detect the changes of Nrf2, ARE, DAT, DA, VMAT2 and ROS in the cerebrospinal fluid, prefrontal cortex and striatum of SHR rats, and then, to clarify the molecular mechanism of baicalin regulates Nrf2/ARE signaling pathway which play the anti-oxidative stress effects to affect DA transmitter transport balance to treat ADHD. So as to provide experimental evidence to clarify the mechanism of baicalin in the treatment of ADHD and contribute the popularization and application of baicalin.