Oxidative stress and neuronal apoptosis have been demonstrated to be key features in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have indicated that Mas receptor activation initiates an anti-oxidative and anti-apoptotic role in the brain. However, whether Mas activation can attenuate oxidative stress and neuronal apoptosis after SAH remains unknown. To investigate the beneficial effect of Mas on oxidative stress injury and neuronal apoptosis induced by SAH, a total of 196 rats were subjected to an endovascular perforation model of SAH. AVE 0991 (AVE), a selective agonist of Mas, was administered intranasally 1 h after SAH induction. A779, a selective inhibitor of Mas, and small interfering ribonucleic acid (siRNA) for UCP-2 were administered by intracerebroventricular (i.c.v) injection at 1 h and 48 h before SAH induction respectively. Neurological tests, immunofluorescence, TUNEL, Fluoro-Jade C, DHE staining, and Western blot experiments were performed. We found that Mas activation with AVE significantly improved neurobehavioral scores and reduced oxidative stress and neuronal apoptosis in SAH+AVE group compared with SAH+vehicle group. Moreover, AVE treatment significantly promoted phosphorylation of CREB and the expression UCP-2, as well as upregulated expression of Bcl-2 and downregulation of Romo-1 and Bax. The protective effects of AVE were reversed by i.c.v injection of A779 and UCP-2 siRNA in SAH+AVE+A779 and SAH+AVE+UCP-2 siRNA groups, respectively. In conclusion, our data provides evidence that Mas activation with AVE reduces oxidative stress injury and neuronal apoptosis through Mas/PKA/p-CREB/UCP-2 pathway after SAH. Furthermore, our study indicates that Mas may be a novel therapeutic treatment target in early brain injury of SAH.

Understanding the origin and maintenance of phenotypic variation, particularly across a continuous spatial distribution, represents a key challenge in evolutionary biology. For this, animal venoms represent ideal study systems: they are complex, variable, yet easily quantifiable molecular phenotypes with a clear function. Rattlesnakes display tremendous variation in their venom composition, mostly through strongly dichotomous venom strategies, which may even coexist within a single species. Here, through dense, widespread population-level sampling of the Mojave rattlesnake, Crotalus scutulatus , we show that genomic structural variation at multiple loci underlies extreme geographical variation in venom composition, which is maintained despite extensive gene flow. Unexpectedly, neither diet composition nor neutral population structure explain venom variation. Instead, venom divergence is strongly correlated with environmental conditions. Individual toxin genes correlate with distinct environmental factors, suggesting that different selective pressures can act on individual loci independently of their co-expression patterns or genomic proximity. Our results challenge common assumptions about diet composition as the key selective driver of snake venom evolution and emphasize how the interplay between genomic architecture and local-scale spatial heterogeneity in selective pressures may facilitate the retention of adaptive functional polymorphisms across a continuous space.

Brain edema is a vital contributor to early brain injury after subarachnoid hemorrhage (SAH), which is responsible for prolonged hospitalization and poor outcomes. Pharmacological therapeutic targets on edema formation have been the focus of research for decades. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to participate in neural development and brain injury. Here, we used PACAP knockout CRISPR to demonstrate that endogenous PACAP plays an endogenous neuroprotective role against brain edema formation after SAH in rats. The exogenous PACAP treatment provided both short-and longterm neurological benefits by preserving the function of the blood-brain barrier and glymphatic system after SAH. Pretreatment of inhibitors of PACAP receptors showed that the PACAP-involved anti-edema effect and neuroprotection after SAH was facilitated by the selective PACAP receptor (PAC1). Further administration of adenylyl cyclase (AC) inhibitor and sulfonylurea receptor 1 (SUR1) CRISPR activator suggested that the AC-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) axis participated in PACAP signaling after SAH, which inhibited the expression of edema-related proteins, SUR1 and aquaporin-4 (AQP4), through SUR1 phosphorylation. Thus, PACAP may serve as a potential clinical treatment to alleviate brain edema in patients with SAH.

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