Neutrophil β₁ 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 β1 adrenoceptors (β1AR) have been linked to neutrophil migration during exacerbated inflammation. Given the central role of neutrophils in cerebral damage during stroke, we hypothesize that β1AR 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 β1AR 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 β1AR 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, β1AR blockade by metoprolol reduced circulating neutrophil–platelet co‐aggregates. Conclusions and Implications Our findings describe that β1AR 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.

Immunothrombosis in neurovascular disease

“…Additionally, it has become evident that not all inflammation is bad in stroke. Not only do neutrophils contribute to immunothrombosis but there is also a subtype of neutrophils that exerts an anti-inflammatory phenotype (N2 neutrophils), a phenotype that is modulated by toll-like receptor 4 signaling [ 82 , 83 ]. Furthermore, neutrophils ameliorate long-term stroke outcomes by releasing cathelicidin antimicrobial peptide, which promotes endothelial cell proliferation and angiogenesis after stroke [ 84 ].…”

Genetically engineered neural stem cells (NSCs) therapy for neurological diseases; state‐of‐the‐art

“…122 Like the majority of common neurological diseases, neuroinflammation is a key pathological effect found in stroke. 123,124 Although NSCs therapy represents a great capacity for the treatment of stroke by inducing neurogenesis, inhibiting neuroinflammation, and sustaining the BBB integrity and angiogenesis, their poor engraftment, survival, and proliferation obstruct their more efficient beneficial influences in vivo. 72,89 Accordingly, the gene engineering of NSC is regarded as a lucid strategy to bypass these hurdles.…”

“…In embolic event, a blood vessel that is affected by an embolism is blocked by debris from elsewhere in the body 122 . Like the majority of common neurological diseases, neuroinflammation is a key pathological effect found in stroke 123,124 …”

Research progress on the role of hormones in ischemic stroke

“…β-blocker was negatively associated with the incidence of nosocomial pneumonia before and during the stroke ( 165 ). β1 adrenergic receptor of neutrophils is associated with migration during increased inflammation, and β1 adrenergic receptor blocking improves brain damage by targeting neutrophils ( 166 ). The β-blocker carvedilol may protect the ischemic brain in the rat by inhibiting apoptosis and attenuating the expression of TNF-α and IL-1β ( 167 ).…”