2. Academic Validation
  3. Activation of TGR5 protects blood brain barrier via the BRCA1/Sirt1 pathway after middle cerebral artery occlusion in rats

Activation of TGR5 protects blood brain barrier via the BRCA1/Sirt1 pathway after middle cerebral artery occlusion in rats

  • J Biomed Sci. 2020 May 8;27(1):61. doi: 10.1186/s12929-020-00656-9.
Hui Liang 1 2,  Nathanael Matei 2,  Devin W McBride 3,  Yang Xu 2,  Jiping Tang 2,  Benyan Luo 4,  John H Zhang 5
Affiliations

Affiliations

  • 1 Department of Neurology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
  • 2 Department of Physiology and Pharmacology and Department of Anesthesiology, Loma Linda University, 11041 Campus St, Risley Hall, Room 219, Loma Linda, CA, 92354, USA.
  • 3 The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, 77030, USA.
  • 4 Department of Neurology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. [email protected].
  • 5 Department of Physiology and Pharmacology and Department of Anesthesiology, Loma Linda University, 11041 Campus St, Risley Hall, Room 219, Loma Linda, CA, 92354, USA. [email protected].
PMID: 32381096 DOI: 10.1186/s12929-020-00656-9
Abstract

Background: 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.

Methods: This 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.

Results: Endogenous 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.

Conclusions: Our 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.

Keywords

BRCA1; Blood-brain barrier; Middle cerebral artery occlusion; Neuroprotection; Sirt1; TGR5.

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