Cholecystokinin-8 attenuates methamphetamine-induced inflammatory activation of microglial cells through CCK2 receptor
Cholecystokinin-8 attenuates methamphetamine-induced inflammatory activation of microglial cells through CCK2 receptor
复制标题
胆囊收缩素-8 通过 CCK2 受体减弱甲基苯丙胺诱导的小胶质细胞炎症活化
DOI：
10.1016/j.neuro.2020.09.001
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发表时间：
2020-12-01
期刊：
影响因子：
3.4
通讯作者：
Wen, Di
中科院分区：
文献类型：
--
作者：
Gou, Hongyan;Sun, Donglei;Wen, Di
据报道，甲基苯丙胺（METH）暴露促进小胶质细胞活化和促炎细胞因子分泌。精神兴奋剂药物滥用者的持续炎症进一步诱导神经损伤。胆囊收缩素-8（cholesterostokinin-8，CCK-8）是一种肠脑肽，在胃肠道和中枢神经系统发挥广泛的生物活性。我们以前发现，CCK-8预处理抑制行为和组织学的变化，通常引起的重复暴露于甲基。在这里，我们的目的是评估CCK-8对METH诱导的神经炎症的影响，其显著特征是小胶质细胞活化和促炎细胞因子的产生增加在体内和体外。此外，我们评估了CCK受体介导CCK-8的调节作用的亚型，以及NF-κ B B信号通路的变化。我们发现CCK-8在体内和体外以剂量依赖性方式抑制MET诱导的小胶质细胞活化和IL-6和TNF-α的产生。此外，CCK-8与METH的共处理通过激活N9细胞中的CCK 2受体亚型而显著减弱NF-κ B信号通路的激活。总之，我们的研究结果表明CCK-8在体内和体外对METH诱导的神经炎症具有抑制作用，并提示其潜在机制可能涉及CCK 2受体的激活，其下调了由METH刺激诱导的NF-κ B信号通路。
Methamphetamine (METH) exposure reportedly promotes microglial activation and pro-inflammatory cytokines secretion. Sustained inflammation in abusers of psychostimulant drugs further induces neural damage. Cholecystokinin-8 (CCK-8) is a gut-brain peptide which exerts a wide range of biological activities in the gastrointestinal tract and central nervous system. We previously found that pre-treatment with CCK-8 inhibited behavioural and histologic changes typically induced by repeated exposure to METH. Here, we aimed to estimate the effects of CCK-8 on METH-induced neuro-inflammation, which is markedly characterized by microglia activation and increased pro-inflammatory cytokines production in vivo and in vitro. Moreover, we assessed the subtypes of the CCK receptor mediating the regulatory effects of CCK-8, and the changes in the NF-kappa B signalling pathway. We found that CCK-8 inhibited METH-induced microglial activation and IL-6 and TNF-alpha generation in vivo and in vitro in a dose-dependent manner. Furthermore, co-treatment of CCK-8 with METH significantly attenuated the activation of the NF-kappa B signalling pathway by activating the CCK2 receptor subtype in N9 cells. In conclusion, our findings indicated the inhibitory effect of CCK-8 on METH-induced neuro-inflammation in vivo and in vitro, and suggested the underlying mechanism may involve the activation of the CCK2 receptor, which downregulated the NF-kappa B signalling pathway induced by METH stimulation.