Carnosine protects against cerebral ischemia/reperfusion injury through promoting microglial M2 polarization via SIRT1/NF-κB signaling pathway.

Ischemic stroke, a leading cause of disability and mortality worldwide, often results in secondary brain injury due to oxidative stress and neuroinflammation following thrombolysis with tissue plasminogen activator (t-PA). Carnosine (CAR), a naturally occurring dipeptide, exhibits anti-inflammatory and neuroprotective properties. But its mechanisms in cerebral ischemia-reperfusion injury (CIRI) remain unclear. In this study, we aim to investigate the role of microglial polarization regulated by SIRT1/NF-κB signaling pathway on CAR therapeutic effect in CIRI. Here, we demonstrate that CAR attenuates neurological deficits and infarct volume in MCAO/R rats while promoting microglial polarization toward the anti-inflammatory M2 phenotype in vitro and in vivo. Mechanistically, CAR activates SIRT1, suppresses NF-κB signaling and downregulates pro-inflammatory cytokines (TNF-α, IL-1β). These effects were reversed by the SIRT1 inhibitor EX527, confirming the pivotal role of the SIRT1/NF-κB pathway. Therefore, our findings highlight CAR's potential as a therapeutic agent for ischemic stroke.