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.

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I ntraventricular hemorrhage (IVH) occurs in 40% of patients with intracerebral hemorrhage (ICH). IVH is a severe complication of ICH 1 and is rarely (<3%) found in the absence of ICH. 2,3 Recent studies have shown that IVH and hydrocephalus are predictors of poor outcome after ICH. 4 Both human studies and preclinical studies on primary IVH or ICH with ventricular extension (ICH/IVH) are rare. However, some clinical studies have indicated that IVH, secondary to ICH, could lead to a higher risk of long term shunt dependent hydrocephalus compared with primary IVH. [5][6][7][8][9] Brain injury and hydrocephalus have not been systematically evaluated in relation to these 2 types of IVH in either humans or animals. 10 Recently, based on the most commonly used primary IVH rat model, we established a rat model of reproducible ICH/ IVH, which features characteristics of both ICH and IVH and closely mimics human IVH. 11Although it is well known that IVH is associated with hydrocephalus, the underlying mechanisms remain unclear. 10Recent studies have indicated that iron may play an important role in posthemorrhagic hydrocephalus and brain injury. [12][13][14][15] After disruption of the brain-cerebrospinal fluid (CSF) barrier because of IVH, intracerebral hematoma may provide a source of iron for release into the ventricular system via this breached barrier, eventually leading to brain damage.Thus, we hypothesized that ICH/IVH would generate more significant hydrocephalus and brain injury than IVH alone. This study examined this hypothesis by comparing the ICH/ IVH rat model with the primary IVH rat model. Moreover, we explored the potential role of intracerebral hematoma in brain iron deposition and hydrocephalus after ICH/IVH. MethodsOne hundred and sixty adult male Sprague-Dawley rats (250-350 g; the Third Military Medical University) were used. Animal use procedures were in compliance with the Guide for the Care and Use of Laboratory Animals and approved by the Animal Care and UseBackground and Purpose-The intraventricular hemorrhage (IVH) secondary to intracerebral hemorrhage (ICH) was reported to be relevant to a higher incidence of hydrocephalus, which would result in poorer outcomes for patients with ICH. However, the mechanisms responsible for this relationship remain poorly characterized. Thus, this study was designed to further explore the development and progression of hydrocephalus after secondary IVH. Methods-Autologous blood injection model was induced to mimic ICH with ventricular extension (ICH/IVH) or primary IVH in Sprague-Dawley rats. Magnetic resonance imaging, Morris water maze, brain water content, Evans blue extravasation, immunohistochemistry staining, Western blot, iron determination, and electron microscopy were used in these rats. Then, deferoxamine treatment was used to clarify the involvement of iron in the development of hydrocephalus. Chen et al Role of Intracerebral Hematoma in Hydrocephalus 2903Committee at the Third Military Medical University. Animals were anesthetized with pento...