Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease that usually has a poor prognosis. Heat shock proteins (HSPs) have been implicated in the mechanisms of SAH-associated damage, including increased inflammation and reduced neurogenesis. The aim of this study was to investigate the effects of HSP90 inhibition on inflammation and neurogenesis in a mouse model of experimental SAH induced by endovascular surgery. Western blotting showed HSP90 levels to be decreased, while neurogenesis, evaluated by 5-bromo-2’-deoxyuridine (BrdU) immunohistochemistry, was decreased in the hippocampuses of SAH mice. SAH also induced pro-inflammatory factors such as interleukin-1β (IL-1β), capase-1 and the NLRP3 inflammasome. However, intraperitoneal administration of the specific HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) reduced the levels of HSP90, NLRP3, ASC, caspase-1 and IL-1β, while increasing the levels of brain-derived neurotrophic factor and doublecortin (DCX), as well as the number of BrdU-positive cells in SAH mice. In addition, 17-AGG improved short- and long-term neurobehavioral outcomes. The neuroprotective and anti-inflammatory effects of 17-AGG were reversed by recombinant HSP90 (rHSP90); this detrimental effect of HSP90 was inhibited by the specific P2X7 receptor (P2X7R) inhibitor A438079, indicating that SAH-induced inflammation and inhibition of neurogenesis were likely mediated by HSP90 and the P2X7R/NLRP3 inflammasome pathway. HSP90 inhibition by 17-AAG may be a promising therapeutic strategy for the treatment of SAH.

Background: Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with poor clinical outcome. Nucleotide binding and oligomerization domainlike receptor family pyrin domain-containing 3 (NLRP3) inflammasome serves a key role in inflammatory response, which may lead to endothelial cell injury and blood-brain barrier (BBB) disruption. Hydrogen (H 2) is considered a neuroprotective antioxidant. This study was set out to explore whether hydrogen inhalation protects against SAH induced endothelial cell injury, BBB disruption, microthrombosis and vasospasm in rats. Methods: One hundred eighty-two male SD rats were used for the study. SAH was induced by endovascular perforation. H2 at a concentration of 3.3% was inhaled beginning at 0.5 h after SAH for duration of 30, 60 or 120 min, followed by single administration or once daily administration for 3 days. The temporal expression of NLRP3 and ASC in the brain was determined, with the effect of hydrogen inhalation evaluated. In addition, brain water content, oxidative stress markers, inflammasome, apoptotic markers, microthrombosis, and vasospasm were evaluated at 24 or 72 h after SAH. Results: The expression of NLRP3 and ASC were upregulated after SAH associated with elevated expression of MDA, 8-OHdG, 4-HNE, HO-1, TLR4/NF-κB, inflammatory and apoptotic makers. Hydrogen inhalation reduced the expression of these inflammatory and apoptotic makers in the vessels, brain edema, microthrombi formation, and vasospasm in rats with SAH relative to control. Hydrogen inhalation also improved short-term and long-term neurological recovery after SAH. Conclusion: Hydrogen inhalation can ameliorate oxidative stress related endothelial cells injury in the brain and improve neurobehavioral outcomes in rats following SAH. Mechanistically, the above beneficial effects might be related to, at least in part, the inhibition of activation of ROS/NLRP3 axis.

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