Article

Inhibition of Rho kinase by hydroxyfasudil attenuates brain edema after subarachnoid hemorrhage in rats

Department of Physiology and Pharmacology, Loma Linda University, 11234 Anderson Street, Loma Linda, CA 92354, USA.
Neurochemistry International (Impact Factor: 3.09). 02/2012; 60(3):327-33. DOI: 10.1016/j.neuint.2011.12.014
Source: PubMed

ABSTRACT

The blood-brain barrier (BBB) disruption and brain edema are important pathophysiologies of early brain injury after subarachnoid hemorrhage (SAH). This study is to evaluate whether Rho kinase (Rock) enhances BBB permeability via disruption of tight junction proteins during early brain injury. Adult male rats were assigned to five groups; Sham-operated, SAH treated with saline, a Rock inhibitor hydroxyfasudil (HF) (10 mg/kg) treatment at 0.5 h after SAH, HF treatment at 0.5 and 6 h (10 mg/kg, each) after SAH, and another Rock inhibitor Y27632 (10 mg/kg) treatment at 0.5 h after SAH. The perforation model of SAH was performed and neurological score and brain water content were evaluated 24 and 72 h after surgery. Evans blue extravasation, Rock activity assay, and western blotting analyses were evaluated 24 h after surgery. Treatment of HF significantly improved neurological scores 24 h after SAH. Single treatment with HF and Y27632, and two treatments with HF reduced brain water content in the ipsilateral hemisphere. HF reduced Evans blue extravasation in the ipsilateral hemisphere after SAH. Rock activity increased 24 h after SAH, and HF reversed the activity. SAH significantly decreased the levels of tight junction proteins, occludin and zonula occludens-1 (ZO-1), and HF preserved the levels of occluding and ZO-1 in ipsilateral hemisphere. In conclusion, HF attenuated BBB permeability after SAH, possibly by protection of tight junction proteins.

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    • "CLDN5 knockout mice presented increased BBB permeability [13]; on the contrary, inhibiting decreased expression of CLDN5 has been shown to reduce brain edema and hemorrhagic transformation [14]. The expressions of ZO- 1 and OCLN were significantly decreased after subarachnoid hemorrhage (SAH) [15], and degrading ZO-1 and OCLN in endothelial tight junction can facilitate capillary leakage, which is responsible for the increase in BBB permeability after SAH [16]. Increased BBB permeability after ICH has been noted in parallel with edema formation and BBB disruption leading to vasogenic edema [17]. "
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    ABSTRACT: Brain injury after intracranial hemorrhage (ICH) results in significant morbidity and mortality. Blood brain barrier (BBB) disruption is a hallmark of ICH-induced brain injury; however, data mirroring BBB disruption in human ICH are scarce. The aim of this study was to assess the significance of circulating biomarkers in evaluating BBB disruption after ICH. Twenty-two patients with ICH were recruited in this study. Concentrations of the tight junction proteins (TJs) Claudin-5 (CLDN5), Occludin (OCLN), and zonula occludens 1 (ZO-1) and vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were measured by using enzyme-linked immunosorbent assay in serum and cerebrospinal fluid (CSF) samples obtained from patients with ICH. The white blood cell (WBC) count in blood and CSF, albumin (ALB) levels in the CSF ( ALB CSF ), and the BBB ratio were significantly higher in the ICH than in controls ( p < 0.05 ). Significantly higher levels of CLDN5, OCLN, ZO-1, MMP-9, and VEGF in CSF were observed in the ICH group; these biomarkers were also positively associated with BBB ratio ( p < 0.05 ). Our data revealed that circulating TJs could be considered the potential biomarkers reflecting the integrity of the BBB in ICH.
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    • "A total of 25 adult male Sprague-Dawley rats (Harlan, Indianapolis, IN) weighing 260–320 g were used for the study. The endovascular perforation model of SAH was performed as previously described [5,6]. Briefly, rats were anesthetized, intubated and kept on artificial ventilation during surgery. "
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