Cocaine use disorder is a major health crisis that is associated with increased oxidative stress and neuroinflammation. While the role of NLRP3 inflammasome in mediating neuroinflammation is well-recognized, whether cocaine induces this response remains unexplored. Based on the premise that cocaine induces both reactive oxygen species (ROS) as well as microglial activation, we hypothesized that cocaine-mediated microglial activation involves both ROS and NLRP3 signaling pathways. We examined activation of the NLRP3 pathway in microglia exposed to cocaine, followed by validation in mice administered either cocaine or saline for 7 days, with or without pretreatment with the NLRP3 inhibitor, MCC950, and in postmortem cortical brain tissues of chronic cocaine-dependent humans. We found that microglia exposed to cocaine exhibited significant induction of NLRP3 and mature IL-1β expression. Intriguingly, blockade of ROS (Tempol) attenuated cocaine-mediated priming of NLRP3 and microglial activation (CD11b). Blockade of NLRP3 by both pharmacological (MCC950) as well as gene silencing (siNLRP3) approaches underpinned the critical role of NLRP3 in cocaine-mediated activation of inflammasome and microglial activation. Pretreatment of mice with MCC950 followed by cocaine administration for 7 days mitigated cocaine-mediated upregulation of mature IL-1β and CD11b, in both the striatum and the cortical regions. Furthermore, cortical brain tissues of chronic cocaine-dependent humans also exhibited upregulated expression of the NLRP3 pathway mediators compared with non-cocaine dependent controls. Collectively, these findings suggest that cocaine activates microglia involving the NLRP3 inflammasome pathway, thereby contributing to neuroinflammation. NLRP3 can thus be considered as a potential therapeutic target for alleviating cocaine-mediated neuroinflammation.

可卡因使用障碍是一种主要的健康危机，与氧化应激和神经炎症增加有关。虽然 NLRP3 炎症小体在介导神经炎症中的作用已广为人知，但可卡因是否诱导这种反应仍有待探索。基于可卡因诱导活性氧 (ROS) 和小胶质细胞活化的前提，我们假设可卡因介导的小胶质细胞活化涉及 ROS 和 NLRP3 信号通路。我们检查了暴露于可卡因的小胶质细胞中 NLRP3 通路的激活，然后在给予可卡因或盐水 7 天的小鼠中进行了验证，有或没有用 NLRP3 抑制剂 MCC950 预处理，以及在慢性可卡因依赖人类的死后皮质脑组织中. 我们发现暴露于可卡因的小胶质细胞表现出对 NLRP3 和成熟 IL-1β 表达的显着诱导。有趣的是，ROS (Tempol) 的阻断减弱了可卡因介导的 NLRP3 启动和小胶质细胞激活 (CD11b)。通过药理学 (MCC950) 和基因沉默 (siNLRP3) 方法阻断 NLRP3 支持了 NLRP3 在可卡因介导的炎症小体激活和小胶质细胞激活中的关键作用。用 MCC950 预处理小鼠，然后给予可卡因 7 天，可减轻可卡因介导的纹状体和皮质区域成熟 IL-1β 和 CD11b 的上调。此外，与非可卡因依赖的对照相比，慢性可卡因依赖人类的皮质脑组织也表现出 NLRP3 通路介质的表达上调。集体，这些发现表明，可卡因激活了涉及 NLRP3 炎症小体通路的小胶质细胞，从而导致了神经炎症。因此，NLRP3 可以被认为是缓解可卡因介导的神经炎症的潜在治疗靶点。