Alisol A Mitigates Neuroinflammation and Oxidative Stress After Subarachnoid Hemorrhage Through SIRT3-Driven Reprogramming of Mitochondrial Metabolism.

Subarachnoid hemorrhage (SAH) is a devastating stroke subtype with high mortality and morbidity, causing severe brain injury through neuroinflammation and oxidative stress. Alisol A, a bioactive compound derived from Alisma orientale, has demonstrated anti-inflammatory, antioxidant, and metabolic-regulating properties. However, the potential role of alisol A in SAH has not yet been explored. This study was conducted to investigate the therapeutic role of alisol A in brain injury induced by SAH, with a particular focus on its underlying metabolic mechanisms. Our results showed that alisol A mitigated neuroinflammation and oxidative stress and alleviated brain injury and neurological deficits in SAH mice. This neuroprotective effect was associated with modulation of mitochondrial metabolism, notably a reduction in succinate accumulation, an important metabolite associated with inflammation and oxidative damage. Supplementation with succinate partially counteracted the observed anti-inflammatory and antioxidant effects of alisol A. Crucially, we identified sirtuin 3 (SIRT3) as an important mediator of these processes. The beneficial effects of alisol A on mitochondrial metabolism, as well as its anti-inflammatory and antioxidant actions, were dependent on SIRT3 upregulation. Overall, our study demonstrated that alisol A could protect against SAH-induced brain injury by upregulating SIRT3 expression, which reprogrammed mitochondrial metabolism and prevented succinate accumulation, thereby reducing neuroinflammation and oxidative stress. These findings deepen our understanding of the metabolic regulatory role of alisol A and highlight its therapeutic potential for SAH and other neurological disorders characterized by neuroinflammation and oxidative stress.