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Neuronal apoptosis is one of the main pathophysiological events in the early brain injury (EBI) post subarachnoid hemorrhage (SAH). Wnt-3a, one of the endogenous wnt ligands crucial in neurogenesis, has been proven to be efficacious in neuroprotection in traumatic brain injury and ischemic stroke. The glycolytic enzyme aldolase C and ribosome biogenesis protein PPAN were revealed to be linked to wnt signaling pathway. The aim of the study was to explore the antiapoptotic effects of intranasal wnt-3a through Frizzled-1 (Frz-1)/aldolase C/PPAN pathway in SAH. Approaches for assessment included SAH grade, Garcia test, brain water content evaluation, rotarod test, Morris water maze test, Western blot, immunofluorescence and transmission electron microscopy. The results showed that wnt-3a improved the neurological scores, brain water content and long-term neurobehavioral functions after SAH. Wnt-3a increased the level of Frz-1, aldolase C, β-catenin, PPAN and the Bcl-2/Bax ratio; and decreased the level of axin and cleaved caspase-3 (CC-3). The anti-apoptotic effect of wnt-3a was further evidenced by TUNEL staining and subcellular structure imaging. Frz-1 siRNA and aldolase C siRNA offset the effects of wnt-3a; and restoration of aldolase C by aldolase C CRISPR in Frz-1 siRNA preconditioned SAH rats salvaged the level of Frz-1, aldolase C, PPAN and reduced axin and CC-3. In summary, intranasal administration of wnt-3a alleviates neuronal apoptosis through Frz-1/aldolase C/PPAN pathway in the EBI of SAH rats. The feasible intranasal route and the long-lasting neuroprotective property of wnt-3a is of great clinical relevance., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Nucleotide oligomerization domain(NOD)-like receptor protein-3(NLRP3) inflammasome is a multiprotein complex, which results in the inflammatory response in early brain injury(EBI) after subarachnoid hemorrhage(SAH). MCC950, a specific NLRP3 inhibitor, plays neuroprotective effects in several central nervous system diseases. However, the role of MCC950 in SAH remains elusive. This study aims to investigate whether MCC950 exerts neuroprotection after experimental SAH and further explore the potential mechanisms. The SAH model was induced by endovascular perforation process using adult male Sprague-Dawley rats. MCC950 was injected intraperitoneally 1 h after SAH with a dose of 10 mg/kg. The results showed that MCC950 significantly ameliorated severe brain edema and neurological dysfunction. Furthermore, MCC950 efficiently reduced NLRP3 inflammasome expression as well as the pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6. In addition, the protective effect of MCC950 was blunted by lipopolysaccharide. In conclusion, our findings suggest that MCC950 alleviated SAH-induced EBI by suppressing inflammation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Early brain injury (EBI) is the primary cause of poor outcome in subarachnoid hemorrhage (SAH) patients. Rolipram, a specific phosphodiesterase-4 inhibitor which is traditionally used as an anti-depressant drug, has been recently proven to exert neuroprotective effects in several central nervous system insults. However, the role of rolipram in SAH remains uncertain. The current study was aimed to investigate the role of rolipram in EBI after SAH and explore the potential mechanism. Adult male Sprague-Dawley rats were subjected to an endovascular perforation process to produce an SAH model. Rolipram was injected intraperitoneally at 2 h after SAH with a dose of 10 mg/kg. We found that rolipram significantly ameliorated brain edema and alleviated neurological dysfunction after SAH. Rolipram treatment remarkably promoted the expression of Sirtuin 1 (SIRT1) while inhibited NF-κB activation. Moreover, rolipram significantly inhibited the activation of microglia as well as down-regulated the expression of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6. In addition, rolipram increased the expression of protective cytokine IL-10. Furthermore, rolipram significantly alleviated neuronal death after SAH. In conclusion, these data suggested that rolipram exerts neuroprotective effects against EBI after SAH via suppressing neuroinflammation and reducing neuronal loss. The neuroprotective effects of rolipram were associated with regulating the SIRT1/NF-κB pathway. Rolipram could be a novel and promising therapeutic agent for SAH treatment.

Phosphodiesterase-4 (PDE4) plays a fundamental role in a range of central nervous system (CNS) insults, however, the role of PDE4 in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The current study was designed to investigate the role of PDE4 in EBI after SAH and explore the potential mechanism. The SAH model in Sprague-Dawley rat was established by endovascular perforation process. Rats were randomly divided into: sham group, SAH?+?vehicle group, SAH?+?rolipram (PDE4 inhibitor) group, SAH?+?rolipram?+?sirtinol (SIRT1 inhibitor) group and SAH?+?rolipram+MK2206 (Akt inhibitor) group. Mortality, SAH grades, neurological function, brain edema, immunofluorescence staining and western blotting were performed. Double fluorescence labeling staining indicated that PDE4 was located predominately in neurons after SAH. Rolipram reduced brain edema, improved neurological function in the rat model of SAH. Moreover, rolipram increased the expression of Sirtuin1 (SIRT1) and up-regulated the phosphorylation of Akt, which was accompanied by the reduction of neuronal apoptosis. Administration of sirtinol inhibited the phosphorylation of Akt. Moreover, all the beneficial effects of rolipram against SAH were abolished by both sirtinol and MK2206. These data indicated that PDE4 inhibition by rolipram protected rats against EBI after SAH via suppressing neuronal apoptosis through the SIRT1/Akt pathway. Rolipram might be an important therapeutic drug for SAH., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease with few effective pharmacotherapies available. Salvia miltiorrhiza, a traditional Chinese medicinal herb, has been widely used to treat cardiovascular diseases for centuries. Recent studies have demonstrated that magnesium lithospermate B (MLB), a bioactive ingredient extracted from Salvia miltiorrhiza, exerts neuroprotective effects in several central nervous system insults. However, little is known about the role of MLB in SAH-induced brain injury and the exact molecular mechanism. In the current study, we studied the neuroprotective effects of MLB in SAH and explored the potential mechanism. Adult male Sprague-Dawley rats were subjected to an endovascular perforation process to produce an SAH model. MLB was administrated intraperitoneally at 30[Formula: see text]min after SAH with a dose of 25[Formula: see text]mg/kg or 50[Formula: see text]mg/kg. We found that administration of MLB significantly attenuated brain edema and neurological deficits after SAH. In addition, immunofluorescence staining demonstrated that MLB dose-dependently inhibited the activation of microglia and reduced neuronal apoptosis. Western blot analysis showed that MLB decreased the expression of inflammatory cytokine TNF-[Formula: see text] and pro-apoptotic protein cleaved caspase-3. More importantly, MLB increased the expression of SIRT1, while inhibited the acetylation of NF-[Formula: see text]B. Furthermore, pretreatment with sirtinol (a selective inhibitor of SIRT1) reversed all the aforementioned effects of MLB after SAH. In conclusion, our results indicated that MLB exerted robust neuroprotective effects against SAH via suppressing neuroinflammation and apoptosis. These neuroprotective effects of MLB against SAH might be exerted via regulating the SIRT1/NF-[Formula: see text]B pathway. MLB or the SIRT1/NF-[Formula: see text]B pathway could be a novel and promising therapeutic strategy for SAH management.

Studies have suggested that blood-brain barrier (BBB) disruption contributes to the pathogenesis of early brain injury after subarachnoid haemorrhage (SAH). Activation of the receptor tyrosine kinase ErbB4 can cause intramembrane proteolysis and release a soluble intracellular domain (ICD) that modulates transcription in the nucleus. This study was carried out to investigate the potential roles of ErbB4 in preserving BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective effects. Endovascular perforation was used to prepare a rat SAH model. The SAH grade, neurological score, brain edema and BBB permeability were evaluated after surgery. Immunohistochemistry was used to determine the localization of ErbB4 and yes-associated protein (YAP). ErbB4 activator Nrg1 isoform β1 (Nrg1β1), Specific ErbB4 siRNA, YAP siRNA and PIK3CB specific inhibitor TGX 221 were used to manipulate the proposed pathway. The expression levels of ErbB4 ICD and YAP were markly increased after SAH. Double immunohistochemistry labeling showed that ErbB4 and YAP were expressed in endothelial cells and neurons. Activation of ErbB4 by Nrg1β1 (dosage 150 ng/kg) treatment promoted the neurobehavioral deficit, alleviated the brain water content and reduced albumin leakage 24 and 72 h after SAH. ErbB4 activation significantly promoted YAP and PIK3CB activity and increased the expression of tight junction proteins Occludin and Claudin-5. Depletion of ErbB4 aggravated neurological impairment and BBB disruption after SAH. The beneficial effects of ErbB4 activation were abolished by YAP small-interfering RNA and specific PIK3CB inhibitor. Activation of ErbB4 improved neurological performance after SAH through the YAP/PIK3CB signaling pathway, this neuroprotective effects may associated with BBB maintenance. [ABSTRACT FROM AUTHOR]