SIRT3-mediated Mitochondrial Regulation Underlies Sonlicromanol's Protection against Cerebral Ischemia-reperfusion Injury in Rats.

Cerebral ischemia-reperfusion (IR) injury is a significant contributor to stroke-related morbidity, driven by mitochondrial dysfunction, oxidative stress, and inflammation. This study investigates the neuroprotective effects of sonlicromanol (Son), a mitochondria-targeted compound, in a rat model of cerebral IR injury, focusing on the role of sirtuin 3 (SIRT3)-mediated mitochondrial and inflammasome regulation. Male Sprague-Dawley rats underwent transient middle cerebral artery occlusion and were assigned to five groups: control, IR, IR + Son, IR + 3-TYP (SIRT3 inhibitor), and IR + 3-TYP + Son. Son was administered intraperitoneally at reperfusion onset, with or without 3-TYP. IR significantly impaired 24 h postreperfusion neuromotor performance, increased infarct size, and disrupted mitochondrial function (membrane potential, Adenosine Triphosphate [ATP]), elevating reactive oxygen species and inflammasome activation (NOD-like receptor family pyrin domain containing 3; interleukin-1 beta, caspase-1, gasdermin-D). Treatment with Son significantly improved neuromotor performance, reduced infarct size, restored mitochondrial function, increased antioxidant defenses (glutathione, manganese superoxide dismutase or MnSOD, peroxiredoxin 3), and attenuated inflammasome-mediated pyroptosis. These effects correlated with upregulated SIRT3, forkhead box O3, and uncoupling protein 2 expression evaluated by Western blot. SIRT3 inhibition with 3-TYP partially reversed Son's benefits, underscoring SIRT3's pivotal role. However, some protective effects persisted despite SIRT3 inhibition, suggesting additional mechanisms. These findings highlight Son's therapeutic potential in mitigating cerebral IR injury through SIRT3-dependent mitochondrial protection and inflammasome suppression, offering insights for stroke treatment development.