Abstract
BackgroundGlibenclamide is a widely used sulfonylurea drug prescribed to treat type II diabetes mellitus. Previous studies have demonstrated that glibenclamide has neuroprotective effects in central nervous system injury. However, the exact mechanism by which glibenclamide acts on the blood–brain barrier (BBB) after intracerebral hemorrhage (ICH) remains unclear. The purpose of this study was to validate the neuroprotective effects of glibenclamide on ICH and to explore the mechanisms underlying these effects.MethodsWe investigated the effects of glibenclamide on experimental ICH using the autologous blood infusion model. Glibenclamide was administrated either immediately or 2 hr after ICH. Brain edema was quantified using the wet–dry method 3 days after injury. BBB integrity was evaluated by Evans Blue extravasation and degradation of the tight junction protein zona occludens‐1 (ZO‐1). mRNA levels of inflammatory cytokines were determined by quantitative polymerase chain reaction. Activation of the nucleotide‐binding oligomerization domain‐like receptor with a pyrin domain 3 (NLRP3) inflammasome and cell viability were also measured in cerebral microvascular endothelial b.End3 cells exposed to hemin. Neurological changes were evaluated by the Garcia score and rotarod test.ResultsAfter ICH, the brain water content, Evans Blue extravasation, and inflammatory cytokines decreased significantly in the ipsilateral hemisphere of the experimental compared to the vehicle group. Glibenclamide treatment and NLRP3 knockdown significantly reduced hemin‐induced activation of the NLRP3 inflammasome, release of extracellular lactate dehydrogenase, apoptosis, and loss of ZO‐1 in b.End3 cells. However, NLRP3 knockdown abolished the protective effect of glibenclamide.ConclusionGlibenclamide maintained BBB integrity in experimental ICH by inhibiting the activation of the NLRP3 inflammasome in microvessel endothelial cells. Our findings will contribute to elucidating the pharmacological mechanism of action of glibenclamide and to developing a novel therapy for clinical ICH.
Highlights
Intracerebral hemorrhage (ICH) is highly prevalent and detrimental to neurological functioning
Our present results demonstrate that gliben‐ clamide attenuated cerebral edema, neuroinflammation, disruption of the blood–brain barrier (BBB), and neurological deficit after intracere‐ bral hemorrhage (ICH)
Glib‐ enclamide reduced hemin‐induced cell death and loss of zona occludens‐1 (ZO‐1) in bEnd.3 cells. These effects were probably due to the regulation of the NLRP3 inflammasome activation
Summary
Intracerebral hemorrhage (ICH) is highly prevalent and detrimental to neurological functioning. The ICH‐induced injurious inflammatory process involves a ster‐ ile inflammatory response triggered by tissue damage that is medi‐ ated through the nucleotide‐binding oligomerization domain‐like receptor with a pyrin domain 3 (NLRP3) inflammasome. Blocking the activation of NLRP3 inflammasome may effectively reduce the severity of ICH injury. Glibenclamide is a widely used sulfonylurea drug employed to treat type II diabetes mellitus that reduces an excessive inflamma‐ tory response by inhibiting sulfonylurea receptor 1 (Sur1) and the regulatory subunit of the KATP channel following central nervous system (CNS) injury (Caffes, Kurland, Gerzanich, & Simard, 2015). One study demonstrated that glibenclamide protects BBB in‐ tegrity, which reduces the extravasated protein‐induced production of proinflammatory mediators and improves neurological outcomes after experimental ICH (Jiang et al, 2017). We tested the hypothesis that glibenclamide attenuates the disruption of the BBB after ICH by inhibiting the activation of the NLRP3 inflammasome
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