基于miR-124/NF-κB/AMPAR轴探讨钩藤碱抗甲基苯丙胺认知损伤的作用及机制

Cognitive dysfunction induced by methamphetamine (METH) abuse is a main factor that leads to failure in the rehabilitation of abusers. Recent studies indicated that inhibition of neuroinflammation could improve METH-induced cognitive impairment which would probably provide a new treatment strategy for METH addiciton. Our previous studies have found that rhynchophylline, an active constituent extracted from traditional Chinese medicine, could improve METH-induced cognitive impairment and reverse the decreased expression of miR-124 in zebrafish. The results of bioinformatics analysis suggested that miR-124 could regulate NF-κB p65 and AMPA receptor subunit 2. Therefore, we speculate that rhynchophylline can inhibit neuroinflammatory responses and reduce glutamate excitotoxicity in the brain by regulating the miR-124/NF-κB/AMPAR axis and exert the protective effects in METH-induced cognitive impairment. This project will study the effect and mechanism of rhynchophylline on improving METH-induced cognitive impairment based on the miR-124/NF-κB/AMPAR axis via the zebrafish models of METH-induced cognitive impairment and fluorescent labeled microglia transgene, the microglia/neuron co-culture system and the aid of behavioral tracking, miRNA and gene inhibition/overexpression and in vivo imaging technologies. This study may provide new potential drug targets for the treatment of METH addiction.

甲基苯丙胺（METH）滥用所致认知障碍是导致成瘾者难以彻底戒断毒瘾的关键原因。近期报道显示抑制神经炎症能改善METH认知损伤，为METH成瘾的治疗提供了一种新策略。本课题组前期研究发现中药活性成分钩藤碱对斑马鱼METH认知损伤有改善作用，且能逆转模型动物脑内降低的miR-124表达。生物信息学分析提示，miR-124对NF-κB p65和AMPAR亚基2均有调控作用。推测钩藤碱可能通过调节miR-124/NF-κB/AMPAR轴，抑制脑内神经炎症反应，降低谷氨酸兴奋性毒性损伤，对METH认知障碍具有保护作用。本项目拟构建METH认知损伤斑马鱼模型、小胶质细胞/神经元共培养体系以及荧光小胶质细胞标记转基因斑马鱼，借助行为学跟踪、miRNA及基因抑制/过表达、活体成像等手段，探讨钩藤碱通过miR-124/NF-κB/AMPAR轴改善METH认知损伤的作用及机制，为METH成瘾的治疗提供新靶点。

甲基苯丙胺（METH）滥用所致认知障碍是导致成瘾者难以彻底戒断毒瘾的关键原因。近期报道显示抑制神经炎症能改善METH认知损伤，为METH成瘾的治疗提供了一种新策略。本课题组前期研究发现中药活性成分钩藤碱对斑马鱼METH认知损伤有改善作用，且能逆转模型动物脑内降低的miR-124表达。生物信息学分析提示，miR-124对NF-κB p65和AMPAR亚基2均有调控作用。推测钩藤碱可能通过调节miR-124/NF-κB/AMPAR轴，抑制脑内神经炎症反应，降低谷氨酸兴奋性毒性损伤，对METH认知障碍具有保护作用。本项目拟构建METH认知损伤斑马鱼模型、小胶质细胞/神经元共培养体系以及荧光小胶质细胞标记转基因斑马鱼，借助行为学跟踪、miRNA及基因抑制/过表达、活体成像等手段，探讨钩藤碱通过miR-124/NF-κB/AMPAR轴改善METH认知损伤的作用及机制，为METH成瘾的治疗提供新靶点。