SS31 Mitigates Subarachnoid Hemorrhage-Induced Early Brain Injury via Nrf2/Keap1 Pathway Activation

Background : Subarachnoid hemorrhage (SAH) presents a significant clinical challenge with high mortality and disability rates. Oxidative stress (OS) plays a critical role in early brain injury post-SAH. SS31, an antioxidant agent, has shown promise in mitigating ischemia/reperfusion injury-related damage. This study aims to investigate the role and mechanism of SS31 in SAH, focusing on its impact on early brain injury. Methods : This study systematically investigated the neuroprotective mechanisms of SS31 through both in vivo and in vitro approaches. Initially, we assessed the anti-apoptotic efficacy of SS31 using a subarachnoid hemorrhage (SAH) rat model and an HB-induced SH-SY5Y microglial cell model, concurrently evaluating its impact on neurological functional recovery in SAH animals. Subsequently, we examined the regulatory effects of SS31 on the KEAP1/Nrf2/HO-1 signaling pathway through protein expression analysis in both experimental systems. Furthermore, ultrastructural and functional evaluations were conducted to characterize SS31's protective effects against mitochondrial impairment in SAH pathogenesis. Results: SS31 treatment significantly mitigated early brain injury (EBI) following SAH, including BBB dysfunction, BE, neural cell apoptosis, OS, mitochondrial damage, and neurological deficits. SS31 also inhibits apoptosis, both in vivo and in cell models. At the same time, SS31 inhibited the expression of inflammatory factors in rat brain tissue and serum, which confirmed its anti-inflammatory effect. Furthermore, SS31 administration resulted in a notable reduction in Keap1 expression and a significant increase in Nrf2 and HO-1 expression. Conclusion: This study demonstrated that SS31 enhanced the recovery of nervous function after SAH in rats by mitigating OS-associated neuronal death via the Nrf2/Keap1 axis.