Microglia, the resident immune cells in the central nervous system, play a critical role under physiological conditions, but they may be activated and exaggerate the pathological development of Parkinson’s disease (PD). Recent reports have suggested that neurokinin 1 receptor (NK1R) is involved in various inflammatory diseases, including PD. However, whether neurokinin 1 (NK1) is involved in the activation of microglial cells remains unclear. In the present study, we found that (1) NK1R is located in microglial cells and upregulated in lipopolysaccharide (LPS)-activated BV2 microglia. Application of CP-99994, a selective antagonist of NK1R, inhibited the production of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), IL-6, inducible macrophage-type nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in activated BV2 cells. (2) NK1R antagonist suppressed the morphological changes in LPS-stimulated BV2. (3) Microglial inactivation by NK1R antagonist resulted in decreased microglial migration. (4) NK1R antagonist reduced nuclear translocation of nuclear factor kappa-B (NF-κB) and attenuated phosphorylation of mitogen-activated protein kinases (MAPKs) in LPS-stimulated BV2. (5) The cell death of PC12 induced by microglia-mediated neuroinflammation was reversed in a Transwell co-culture system by NK1R antagonist. Collectively, these results showed that inhibition of NK1R attenuates LPS-induced microglial inflammatory response and dopaminergic neurotoxicity, which may be due to the decreased MAPK/NF-κB signal pathway. Thus, NK1R may be a therapeutic target in neuroinflammation, especially in PD.

小胶质细胞是中枢神经系统中的常驻免疫细胞，在生理条件下发挥关键作用，但它们可能被激活并夸大帕金森病 (PD) 的病理发展。最近的报道表明，神经激肽 1 受体 (NK1R) 与多种炎症性疾病有关，包括 PD。然而，神经激肽 1 (NK1) 是否参与小胶质细胞的激活仍不清楚。在本研究中，我们发现 (1) NK1R 位于小胶质细胞中，并在脂多糖 (LPS) 激活的 BV2 小胶质细胞中上调。应用 CP-99994（一种 NK1R 的选择性拮抗剂）抑制炎症介质的产生，如肿瘤坏死因子-α (TNF-α)、白细胞介素 1β (IL-1β)、IL-6、诱导型巨噬细胞型一氧化氮合成酶（iNOS），和活化 BV2 细胞中的环氧合酶-2 (COX-2)。(2) NK1R 拮抗剂抑制 LPS 刺激的 BV2 的形态变化。(3) NK1R 拮抗剂对小胶质细胞的灭活导致小胶质细胞迁移减少。(4) NK1R 拮抗剂减少了 LPS 刺激的 BV2 中核因子 kappa-B (NF-κB) 的核易位并减弱了丝裂原活化蛋白激酶 (MAPK) 的磷酸化。(5) NK1R拮抗剂在Transwell共培养系统中逆转小胶质细胞介导的神经炎症诱导的PC12细胞死亡。总的来说，这些结果表明 NK1R 的抑制减弱了 LPS 诱导的小胶质细胞炎症反应和多巴胺能神经毒性，这可能是由于 MAPK/NF-κB 信号通路的减少。因此，NK1R 可能是神经炎症的治疗靶点，尤其是在 PD 中。