SS31 Confers Cerebral Protection by Reversing Mitochondrial Dysfunction in Early Brain Injury Following Subarachnoid Hemorrhage, via the Nrf2-and PGC-1α-Dependent Pathways

In early brain injury (EBI), oxidative stress occurs following subarachnoid hemorrhage (SAH), and mitochondria are intricately linked to this process. SS31, a mitochondria-targeting antioxidative peptide, has been demonstrated to be beneficial for multiple diseases because of its powerful antioxidant and neuroprotective properties. Although our previous study revealed that SS31 was involved in the powerful antioxidant effect following SAH, the underlying molecular mechanisms remained unclear. Thus, our study aimed to investigate the neuroprotective effects of SS31 by reversing mitochondrial dysfunction in EBI following SAH, via activating the Nrf2 signaling and PGC-1 alpha pathways. Our findings confirmed that SS31 ameliorated SAH-triggered oxidative insult. SS31 administration decreased redundant reactive oxygen species, alleviated lipid peroxidation, and elevated the activities of antioxidant enzymes. Concomitant with the inhibited oxidative insult, SS31 dramatically attenuated neurological deficits, cerebral edema, neural apoptosis, and blood-brain barrier disruption following SAH. Moreover, SS31 remarkably promoted nuclear factor-erythroid 2 related factor 2 (Nrf2) nuclear shuttle and upregulated the expression levels of heme oxygenase-1 and NADPH: quinine oxidoreductase1. Additionally, SS31 enhanced the expression levels of PGC-1 alpha and its target genes, and increased the mtDNA copy number, promoting mitochondrial function. However, PGC-1 alpha-specific inhibitor SR-18292 pretreatment dramatically suppressed SS31-induced Nrf2 expression and PGC-1 alpha activation. Furthermore, pretreatment with SR-18292 reversed the neuroprotective and antioxidant roles of SS31. These significant beneficial effects were associated with the activation of the Nrf2 signaling and PGC-1 alpha pathways and were antagonized by SR-18292 administration. Our findings reveal that SS31 exhibits its neuroprotective activity by reversing mitochondrial dysfunction via activating the Nrf2 signaling pathway, which could be mediated through PGC-1 alpha activation.