Astaxanthin (ATX) has been proven to ameliorate early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH) by modulating cerebral oxidative stress. This study was performed to assess the effect of ATX on the Nrf2-ARE pathway and to explore the underlying molecular mechanisms of antioxidant properties of ATX in EBI after SAH. A total of 96 male SD rats were randomly divided into four groups. Autologous blood was injected into the prechiasmatic cistern of the rat to induce an experimental SAH model. Rats in each group were sacrificed at 24 h after SAH. Expressions of Nrf2 and heme oxygenase-1 (HO-1) were measured by Western blot and immunohistochemistry analysis. The mRNA levels of HO-1, NAD (P) H: quinone oxidoreductase 1 (NQO-1), and glutathione S-transferase-α1 (GST-α1) were determined by real-time polymerase chain reaction (PCR). It was observed that administration of ATX post-SAH could up-regulate the cortical expression of these agents, mediated in the Nrf2-ARE pathway at both pretranscriptional and posttranscriptional levels. Meanwhile, oxidative damage was reduced. Furthermore, ATX treatment significantly attenuated brain edema, blood–brain barrier (BBB) disruption, cellular apoptosis, and neurological dysfunction in SAH models. This study demonstrated that ATX treatment alleviated EBI in SAH model, possibly through activating the Nrf2-ARE pathway by inducing antioxidant and detoxifying enzymes.

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SS-31, a novel mitochondria-targeted peptide, has been proven to provide neuroprotection in a variety of neurological diseases. Its role as a mitochondrial reactive oxygen species (ROS) scavenger and the underlying pathophysiological mechanisms in traumatic brain injury (TBI) are still not well understood. The aim of the designed study was to investigate the potential neuroprotective effects of SS-31 and fulfill our understanding of the process of the mitochondrial change in the modified Marmarou weight-drop model of TBI. Mice were randomly divided into sham, TBI, TBI + vehicle, and TBI + SS-31 groups in this study. Peptide SS-31 (5 mg/kg) or vehicle was intraperitoneally administrated 30 min after TBI with brain samples harvested 24 h later for further analysis. SS-31 treatment significantly reversed mitochondrial dysfunction and ameliorated secondary brain injury caused by TBI. SS-31 can directly decrease the ROS content, restore the activity of superoxide dismutase (SOD), and decrease the level of malondialdehyde (MDA) and the release of cytochrome c, thus attenuating neurological deficits, brain water content, DNA damage, and neural apoptosis. Moreover, SS-31 restored the expression of SIRT1 and upregulated the nuclear translocation of PGC-1α, which were proved by Western blot and immunohistochemistry. Taken together, these data demonstrate that SS-31 improves the mitochondrial function and provides neuroprotection in mice after TBI potentially through enhanced mitochondrial rebiogenesis. The present study gives us an implication for further clinical research.