Methamphetamine (METH) is a major public health and safety problem worldwide. METH is psychostimulant that activates microglia via the toll-like receptor (TLR) 4/MD2 complex, modulating the abundant production of pro-inflammatory cytokines in the central nervous system (CNS). The TLR4/MD2 complex on the surface of microglia recognizes pathogen-associated molecular patterns such as lipopolysaccharide (LPS) resulting in brain tissue inflammation and neuronal damage. Since METH has been associated with microglia-induced neurotoxicity, we hypothesized that METH impairs the expression of TLR4 and activation of NF-κB in NR-9460 microglia-like cells after LPS challenge. We demonstrated that METH decreases the distribution and expression of TLR4 receptors on the surface of microglia-like cells after incubation with endotoxin. Moreover, METH impairs the TLR4/MD2 complex signaling pathways, compromises the activation of NF-κB, and reduces the production of pro-inflammatory mediators in microglia-like cells upon LPS stimulation. Interestingly, microglia-like cells treated with METH and challenged with LPS showed considerable cellular morphological changes including enlarged nuclei and ruffled surface. Our results suggest that METH may have a significant impact on microglial-induced neuroinflammation, neurotoxicity, and the CNS defense against infection. It also highlights the importance of studying the effects of METH on the molecular and cellular components of users' CNS immunity. Finally, animal studies exploring the role of METH on the effectors functions of microglia after antigenic exposure are necessary to understand drug-related inflammation and neural damage in users.

中文翻译：

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甲基苯丙胺改变了LPS挑战的NR-9460小胶质细胞样细胞中的TLR4信号通路，NF-κB活化和促炎性细胞因子的产生。

甲基苯丙胺（METH）是全球范围内的主要公共卫生和安全问题。METH是一种精神刺激药，可通过Toll样受体（TLR）4 / MD2复合物激活小胶质细胞，调节中枢神经系统（CNS）中促炎性细胞因子的大量产生。小胶质细胞表面的TLR4 / MD2复合物可识别与病原体相关的分子模式，例如脂多糖（LPS），从而导致脑组织炎症和神经元损伤。由于METH与小胶质细胞引起的神经毒性有关，因此我们假设LETH攻击后METH会损害NR-9460小胶质细胞中TLR4的表达和NF-κB的激活。我们证明，与内毒素一起孵育后，METH会减少小胶质细胞样细胞表面上TLR4受体的分布和表达。此外，METH会损害TLR4 / MD2复杂的信号通路，损害NF-κB的激活，并降低LPS刺激后小胶质样细胞中促炎性介质的产生。有趣的是，用METH处理并用LPS攻击的小胶质细胞样细胞表现出相当大的细胞形态变化，包括核增大和表面皱纹。我们的研究结果表明，甲乙二胺可能对小胶质细胞诱导的神经炎症，神经毒性和中枢神经系统抗感染的防御能力有重大影响。它还强调了研究METH对使用者CNS免疫力的分子和细胞成分的影响的重要性。最后，动物研究探索在抗原暴露后METH对小胶质细胞的效应子功能的作用，对于了解使用者中与药物相关的炎症和神经损伤是必要的。