Abstract
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.
Highlights
Cerebral infarction is one of the leading causes of death and permanent disability worldwide[1]
These studies point to a role of thromboxane A2 receptor (TXA2R) in neuroimmune modulation after stroke and we hypothesize that TXA2R participates in the processes of ischemia/reperfusion-induced microglia/ macrophages activation and enrichment
TXA2R in microglia/macrophages was upregulated in the ipsilateral striatum after transient middle cerebral artery occlusion (tMCAO)
Summary
Cerebral infarction is one of the leading causes of death and permanent disability worldwide[1]. Neuroinflammation mediated by activation of microglia/macrophages is an important factor that contributes to neuron death and infarct area diffusion in ischemia/reperfusion injury[3,4]. Thromboxane biosynthesis was increased in patients with cerebral infarction[16,17] These studies point to a role of TXA2R in neuroimmune modulation after stroke and we hypothesize that TXA2R participates in the processes of ischemia/reperfusion-induced microglia/ macrophages activation and enrichment. The function of TXA2R antagonists in ischemia/reperfusion-induced microglia/macrophages activation and enrichment is unknown. Microglia/macrophages are the main target of the inflammatory response, our study was undertaken to: (1) elucidate the expression changes of TXA2R in a mouse model of ischemic/reperfusion brain injury (transient middle cerebral artery occlusion, tMCAO); (2) assess the function of TXA2R antagonist to microglia/macrophages activation and enrichment, inflammatory response, and the damage after tMCAO
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