Abstract
BackgroundThe disruption of the blood–brain barrier (BBB) plays a critical event in the pathogenesis of ischemia stroke. TGR5 is recognized as a potential target for the treatment for neurologic disorders.MethodsThis study investigated the roles of TGR5 activation in attenuating BBB damage and underlying mechanisms after middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were subjected to model of MCAO and TGR5 agonist, INT777, was administered intranasally. Small interfering RNA (siRNA) for TGR5 and BRCA1 were administered through intracerebroventricular injection 48 h before MCAO. Infarct volumes, brain water content, BBB permeability, neurological scores, Western blot, immunofluorescence staining and co- immunoprecipitation were evaluated.ResultsEndogenous TGR5 and BRCA1 were upregulated in the injured hemisphere after MCAO and TGR5 expressed in endothelial cells. Treatment with INT777 alleviated brain water content and BBB permeability, reduced infarction volume and improved neurological scores at 24 h and 72 h after ischemia. INT777 administration increased BRCA1 and Sirt1 expression, as well as upregulated expressions of tight junction proteins. Ischemic damage induced interaction of TGR5 with BRCA1. TGR5 siRNA and BRCA1 siRNA significantly inhibited expressions of BRCA1 and Sirt1, aggravated BBB permeability and exacerbated stroke outcomes after MCAO. The protective effects of INT777 at 24 h after MCAO were also abolished by TGR5 siRNA or BRCA1 siRNA.ConclusionsOur findings demonstrate that activating TGR5 could reduce BBB breakdown and improve neurological functions through BRCA1/Sirt1 signaling pathway after MCAO. TGR5 may serve as a potential new candidate to relieve brain injury after MCAO.
Highlights
The disruption of the blood–brain barrier (BBB) plays a critical event in the pathogenesis of ischemia stroke
The right common carotid artery (CCA), internal carotid artery (ICA) and external carotid artery (ECA) were surgically exposed. 4–0 nylon suture with silicon was inserted into the ICA through the ECA stump until the tip of the suture reached the origin of the anterior cerebral artery (ACA)
Endogenous TGR5 receptor and BRCA1 expression increased after middle cerebral artery occlusion (MCAO) We investigated TGR5 and BRCA1 alterations after MCAO
Summary
The disruption of the blood–brain barrier (BBB) plays a critical event in the pathogenesis of ischemia stroke. TGR5 is recognized as a potential target for the treatment for neurologic disorders. It has been recognized that disruption of the blood–brain barrier (BBB) is a critical event in the pathogenesis of stroke [2, 3]. The disruption of BBB can lead to extravasation of solutes and fluids into the brain, resulting in vasogenic edema [4], which causes a poor clinical outcome. TGR5 is recognized as a potential target for the treatment for hepatic disorders, metabolic disorders, and kidney disease, through anti-inflammation, anti-apoptosis and inhibition of oxidative stress [8, 9]. The effects of TGR5 on BBB integrity in brain injuries after ischemic stroke have not been investigated
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