Inhibition of NK1R attenuates LPS-induced microglial inflammation and consequent death of PC12 cells

Weifeng Jiang, Xiaoying Wang, Wei Wang, Fang Hua, Zunsheng Zhang, Zuohui Zhang, Jie Xiang, Xinxin Yang
Brain Research Bulletin 2020 June 12
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.

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