Adenosine A1 receptor agonist alleviates cerebral ischemia/reperfusion injury by inhibiting Nrf2/NLRP3 signaling‑mediated pyroptosis

The present study aimed to investigate whether adenosine A1 receptor (A1R) agonists can alleviate cerebral ischemia/reperfusion (I/R) injury by inhibiting pyroptosis mediated through the nuclear factor erythroid 2-related factor 2 (Nrf2)/NLR family pyrin domain containing 3 (NLRP3) signaling pathway. A total of 36 Sprague-Dawley rats were randomly assigned to the following four groups: Sham (sham group), I/R (model group), adenosine A1 receptor agonist preconditioning [model + adenosine A1R agonist 2-chloro-N(6)-cyclopentyladenosine] group and ML385 (model + adenosine A1R agonist group + Nrf2 pathway inhibitor group). A middle cerebral artery occlusion model was induced using the thread occlusion method. Neurological function was assessed using the Longa scale, brain infarction volume was determined through 2,3,5-triphenyltetrazolium chloride staining, protein expression of Nrf2, NLRP3, caspase-1, GSDMD and IL-1β was assessed using western blotting, and the expression of Nrf2 and GSDMD was assessed using immunofluorescence. The findings revealed that adenosine A1R agonist improved neurological function and reduced infarct size. Mechanistically, this was found to be associated with the activation of the Nrf2/NLRP3 signaling pathway and the suppression of pyroptosis-associated proteins (gasdermin D, caspase-1 and IL-1β) expression. Notably, the Nrf2 inhibitor ML385 reversed the aforementioned effects induced by the adenosine A1R agonist. These results suggest that adenosine A1R agonist can alleviate cerebral I/R injury in rats, potentially by modulating the Nrf2/NLRP3 signaling pathway to inhibit pyroptosis.