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-κB signalling pathway. We found that CCK-8 inhibited METH-induced microglial activation and IL-6 and TNF-α 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-κB 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-κB signalling pathway induced by METH stimulation.

据报道，甲基苯丙胺 (METH) 暴露会促进小胶质细胞活化和促炎细胞因子的分泌。精神兴奋剂滥用者的持续炎症会进一步诱发神经损伤。Cholecystokinin-8 (CCK-8) 是一种肠脑肽，在胃肠道和中枢神经系统中发挥广泛的生物活性。我们之前发现，用 CCK-8 预处理可以抑制通常由反复接触 METH 引起的行为和组织学变化。在这里，我们旨在评估 CCK-8 对 METH 诱导的神经炎症的影响，其特征是小胶质细胞激活和体内和体外促炎细胞因子的产生增加. 此外，我们评估了 CCK 受体介导 CCK-8 调节作用的亚型，以及 NF-κB 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 METH 诱导的小胶质细胞活化以及 IL-6 和 TNF-α 的产生。此外，CCK-8 与 METH 的共同处理通过激活 N9 细胞中的 CCK2 受体亚型显着减弱了 NF-κB 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 诱导的神经炎症有抑制作用， 并提出潜在机制可能涉及 CCK2 受体的激活，该受体下调 METH 刺激诱导的 NF-κB 信号通路。