Neutrophil ?1 adrenoceptor blockade blunts stroke-associated neuroinflammation

Abstract

Background and Purpose: Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage. Neutrophil ?1 adrenoceptors (?1AR) have been linked to neutrophil migration during exacerbated inflammation. Given the central role of neutrophils in cerebral damage during stroke, we hypothesize that ?1AR blockade will improve stroke outcomes. Experimental Approach: Rats were subjected to middle cerebral artery occlusion-reperfusion to evaluate the effect on stroke of the selective ?1AR blocker metoprolol (12.5 mg·kg?1) when injected i.v. 10 min before reperfusion. Key Results: Magnetic resonance imaging and histopathology analysis showed that pre-reperfusion i.v. metoprolol reduced infarct size. This effect was accompanied by reduced cytotoxic oedema at 24 h and vasogenic oedema at 7 days. Metoprolol-treated rats showed reduced brain neutrophil infiltration and those which infiltrated displayed a high proportion of anti-inflammatory phenotype (N2, YM1+). Additional inflammatory models demonstrated that metoprolol specifically blocked neutrophil migration via ?1AR and excluded a significant effect on the glia compartment. Consistently, metoprolol did not protect the brain in neutrophil-depleted rats upon stroke. In patients suffering an ischaemic stroke, ?1AR blockade by metoprolol reduced circulating neutrophil-platelet co-aggregates. Conclusions and Implications: Our findings describe that ?1AR blockade ameliorates cerebral damage by targeting neutrophils, identifying a novel therapeutic target to improve outcomes in patients with stroke. This therapeutic strategy is in the earliest stages of the translational pathway and should be further explored.