Role of Glibenclamide in Brain Injury After Intracerebral Hemorrhage

Abstract

Brain edema following intracerebral hemorrhage (ICH) causes severe secondary brain injury, and no efficient pharmacological preventions are available. The present study was designed to demonstrate the neuroprotective effects of glibenclamide on brain edema and key factors of the blood-brain barrier (BBB). The study was divided into two parts. First, we utilized an autoblood-induced rat model to investigate the expression of sulfonylurea receptor 1 (Sur1). Second, rats were randomized into sham, vehicle, and glibenclamide groups. Neurological scores, brain water content, Evans blue extravasation, Morris water maze test, western blots, and immunofluorescence were used to study the effects of glibenclamide. The expression of the Sur1-Trpm4 channel but not the Sur1-KATP channel was increased in the perihematomal tissue following ICH. Glibenclamide administration significantly decreased the brain water content, restored the BBB, and reduced the expression of MMPs. In addition, glibenclamide improved long-term cognitive deficits following ICH. Glibenclamide protected BBB integrity and improved neurological outcomes after ICH by inhibiting the Sur1-Trpm4 channel, which reduces the expression of MMPs and thereby increases BBB tight-junction protein levels. Glibenclamide may have potential to protect the BBB after ICH.

Glibenclamide ameliorates the disrupted blood–brain barrier in experimental intracerebral hemorrhage by inhibiting the activation of NLRP3 inflammasome

“…In addition to its hypoglycemic effects, glibenclamide has been shown to play a protective role in inflammation‐related disorders, particularly in CNS injury, including traumatic brain injury (Patel, Gerzanich, Geng, & Simard, ; Xu et al, ), ischemia‐reperfusion injury (Abdallah, Nassar, & Abd‐El‐Salam, ; Caffes et al, ; Gao et al, ; Yang et al, ), subarachnoid hemorrhage (SAH) (Simard et al, ; Tosun et al, ), and ICH (Jiang et al, ; Ma et al, ). Glibenclamide significantly attenuates neuroinflammation, decreases disruption of the BBB, and improves memory function by blocking the Sur1–Trpm4 channel in both experimental SAH and ICH (Zhou, Shi, Wang, Chen, & Zhang, ).…”

“…Additionally, glibenclamide was suggested to effectively inhibit inflammatory cells migration by inhibiting NLRP3 inflammasome assembly, thereby reducing inflammatory cells infiltration and preventing further organ damage in ischemic tissue (Gao et al, ; Satoh, Kambe, & Matsue, ). One study demonstrated that glibenclamide protects BBB integrity, which reduces the extravasated protein‐induced production of proinflammatory mediators and improves neurological outcomes after experimental ICH (Jiang et al, ). Therefore, we tested the hypothesis that glibenclamide attenuates the disruption of the BBB after ICH by inhibiting the activation of the NLRP3 inflammasome.…”

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence

“…Unlike many other constitutively expressed SUR1 regulated channels in various systemic tissues, SUR1-TRPM4 is unique in that it is not normally present in the CNS, but undergoes de novo upregulation after CNS injury [36]. Upregulation of SUR1 with or without TRPM4 (hereafter SUR1±TRPM4) has been demonstrated in multiple CNS cell types (neurons, astrocytes, endothelial cells, macrophages, microglia) and models of injury, including ischemic stroke [56][57][58][59], TBI [50,[60][61][62], spinal cord injury (SCI) [63,64], intracerebral hemorrhage (ICH) [65], subarachnoid hemorrhage (SAH) [66,67], CNS metastases [68], cardiac arrest [69,70], hepatic failure [71], and encephalomyelitis [72][73][74] ( Figure 1A). The increased expression in several cell-types of the neurovascular unit renders SUR1-TRPM4 a likely contributor across the spectrum of cerebral edema endotypes (reviewed elsewhere [14,15,75]), including cellular/cytotoxic edema, ionic edema, vasogenic edema, and eventually hemorrhagic transformation/progression with complete disintegration of the BBB and oncotic death of endothelial cells ( Figure 1C) [14,15,76].…”

Roles of autophagy and endoplasmic reticulum stress in intracerebral hemorrhage‐induced secondary brain injury in rats

“…Therefore, prevention of SBI after ICH is very valuable . Studies on molecular mechanisms of SBI after ICH may provide new targets for the treatment of patients with ICH . Neuronal damage and apoptosis are important pathological process in SBI after ICH.…”