Effects and mechanisms of long-acting glucagon-like peptide-1 receptor agonist semaglutide on microglia phenotypic transformation and neuroinflammation after cerebral ischemia/reperfusion in rats.

Background: The optimal method for addressing cerebral ischemic stroke involves promptly restoring blood supply. However, cerebral ischemia-reperfusion injury (CIRI) is an unavoidable consequence of this event. Neuroinflammation is deemed the primary mechanism of CIRI, with various activation phenotypes of microglia playing a pivotal role. Research has demonstrated that long-lasting agonists of the glucagon-like peptide-1 receptor can suppress neuroinflammation and microglial activation.

Methods: A transient middle cerebral artery occlusion (tMCAO) rat model was established to investigate the effects of semaglutide. Neurological impairments were evaluated utilizing modified neurological severity score on days 1, 3, and 7 postinterventions. Brains were stained with 2,3,5-Triphenyltetrazolium Chloride to determine infarct volume. To assess the expression of various microglia activation phenotypes and neuroinflammatory biomarkers, we utilized immunohistochemistry and immunoblotting.

Results: The study demonstrated that semaglutide in the tMCAO model could decrease neurological deficit scores and reduce the size of cerebral infarcts. In addition, we observed low levels of cluster of differentiation 68 (CD68, an indicator of M1 microglial activation) and tumor necrosis factor alpha (a pro-inflammatory mediator). Moreover, the results indicated a rise in the levels of CD206 (an indicator of M2 activation) and transforming growth factor beta (an anti-inflammatory mediator), while simultaneously reducing P65 levels in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling cascade.

Conclusion: In the CIRI model, semaglutide exhibits notable neuroprotective effects on rats, reducing neuroinflammation through the regulation of microglia phenotype transformation and inhibition of NF-κB activation.