Thromboxane A2 receptor antagonist SQ29548 reduces ischemic stroke-induced microglia/macrophages activation and enrichment, and ameliorates brain injury

• Published in: Scientific reports Vol. 6; no. 1; p. 35885
• Main Authors: Yan, Aijuan, Zhang, Tingting, Yang, Xiao, Shao, Jiaxiang, Fu, Ningzhen, Shen, Fanxia, Fu, Yi, Xia, Weiliang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-10-2016; Nature Publishing Group
• Subjects: 13/21; 13/51; 631/154/556; 631/378/1689/534; 82; 82/80; Animals; Brain injury; Cell activation; Cerebral blood flow; Cerebral infarction; Cytokines - analysis; Disease Models, Animal; Gliosis - prevention & control; Hemostasis; Humanities and Social Sciences; Hydrazines - administration & dosage; Hydrazines - pharmacology; Immunofluorescence; Inflammation; Interleukin 6; Ischemia; Macrophage Activation; Macrophages; Metabolic pathways; Mice, Inbred ICR; Microglia; multidisciplinary; Nitric-oxide synthase; Polymerase chain reaction; Receptors, Thromboxane A2, Prostaglandin H2 - antagonists & inhibitors; Reperfusion; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Rodents; Science; Stroke; Stroke - complications; Stroke - drug therapy; Stroke - pathology; Thromboembolism; Thrombosis; Thromboxane A2; Traumatic brain injury; Treatment Outcome; Tumor necrosis factor; Ventricle; Ventricles (cerebral)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep35885

Thromboxane A2 receptor (TXA2R) activation is thought to be involved in thrombosis/hemostasis and inflammation responses. We have previously shown that TXA2R antagonist SQ29548 attenuates BV2 microglia activation by suppression of ERK pathway, but its effect is not tested
in vivo
. The present study aims to explore the role of TXA2R on microglia/macrophages activation after ischemia/reperfusion brain injury in mice. Adult male ICR mice underwent 90-min transient middle cerebral artery occlusion (tMCAO). Immediately and 24 h after reperfusion, SQ29548 was administered twice to the ipsilateral ventricle (10 μl, 2.6 μmol/ml, per dose). Cerebral infarction volume, inflammatory cytokines release and microglia/macrophages activation were measured using the cresyl violet method, quantitative polymerase chain reaction (qPCR), and immunofluorescence double staining, respectively. Expression of TXA2R was significantly increased in the ipsilateral brain tissue after ischemia/reperfusion, which was also found to co-localize with activated microglia/macrophages in the infarct area. Administration of SQ29548 inhibited microglia/macrophages activation and enrichment, including both M1 and M2 phenotypes, and attenuated ischemia-induced IL-1ß, IL-6, and TNF-α up-regulation and iNOS release. TXA2R antagonist SQ29548 inhibited ischemia-induced inflammatory response and furthermore reduced microglia/macrophages activation and ischemic/reperfusion brain injury.