期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 513, 期 2, 页码 479-485出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2019.03.202
关键词
Stroke; Inflammation; vx-765; Microglia
资金
- National Natural Science Foundation of China [81820108014, 81771361, 81571166]
Stroke is a life-threatening neurological disease with limited therapeutic options. Inflammation is believed to be involved in the pathogenesis of ischemic stroke and contribute to the degree of brain injury. Vx-765 is a potent, selective, small-molecule caspase-1 inhibitor. Current studies have shown the anti-inflammatory properties of vx-765 in various disease; however, the impact of vx-765 on the ischemic stroke is still unclear. In the present study, we determine the neuroprotective effect of vx-765 in mice subjected to transient middle cerebral artery occlusion (MCAO). We found that caspase-1 inhibition by administration of vx-765 ameliorated cerebral injury in mice after ischemic stroke by reducing infarct volume and ameliorating the neurological deficits. Mechanistically, we showed that the contribution of vx-765 to ischemic injuries may be associated with reducing microglial activation, and downregulating the production of associated pro inflammatory cytokines including IL-1 beta, TNF-alpha, and iNOS, as well as upregulating anti-inflammatory cytokines such as TGF-1 beta and YM-1. Additionally, vx-765 altered the phenotype of microglia via switching the microglia polarization toward M2 phenotype, as demonstrably related to inhibition of the NF-kappa B activation. Our findings indicate that vx-765 protects against MCAO injury and attenuated microglia mediated neuroinflammation primarily by shifting microglia polarization from M1 phenotype toward M2 phenotype. Vx-765 might be a potential therapeutic drug for ameliorating ischemic stroke. (C) 2019 Elsevier Inc. All rights reserved.
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