title: Limb Ischemic Perconditioning Attenuates Blood-Brain Barrier Disruption by Inhibiting Activity of MMP-9 and Occludin Degradation after Focal Cerebral Ischemia.
abstract: Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, however, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, total 90 adult male Sprague Dawley (SD) rats were used. The rats underwent 90-min middle cerebral artery occlusion (MCAO), and the limb remote ischemic PerC was immediately applied after the onset of MCAO. We found that limb remote PerC protected BBB breakdown and brain edema, in parallel with reduced infarct volume and improved neurological deficits, after MCAO. Immunofluorescence studies revealed that MCAO resulted in disrupted continuity of claudin-5 staining in the cerebral endothelial cells with significant gap formation, which was significantly improved after PerC. Western blot analysis demonstrated that expression of tight junction (TJ) protein occludin was significantly increased, but other elements of TJ proteins, claudin-5 and ZO-1, in the BBB endothelial cells were not altered at 48 h after PerC, compared to MCAO group. The expression of matrix metalloproteinase (MMP-9), which was involved in TJ protein degradation, was decreased after PerC. Interestingly, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream of MMP-9 signaling, was significantly reduced in the PerC group. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke.
authors.affiliation: 1 Institute of Hypoxia Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China ; 2 Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA ; 6 Center of Stroke, Beijing Institute for Brain Disorder, Beijing, China ; 7 Beijing Key Laboratory of Hypoxia Translational Medicine. Beijing, China.
authors.forename: Changhong
authors.initials: C
authors.lastname: Ren
authors.affiliation: 1 Institute of Hypoxia Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China ; 6 Center of Stroke, Beijing Institute for Brain Disorder, Beijing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: 2 Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Wang
authors.affiliation: 3 Department of Herbal Medicine, School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 1 Institute of Hypoxia Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China.
authors.forename: Jinhuan
authors.initials: J
authors.lastname: Gao
authors.affiliation: 1 Institute of Hypoxia Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China ; 6 Center of Stroke, Beijing Institute for Brain Disorder, Beijing, China.
authors.forename: Sijie
authors.initials: S
authors.lastname: Li
authors.affiliation: 4 Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: 1 Institute of Hypoxia Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China ; 2 Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Kunlin
authors.initials: K
authors.lastname: Jin
authors.affiliation: 1 Institute of Hypoxia Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China ; 5 Cerebrovascular Diseases Research Institute, Xuanwu Hospital, Capital Medical University, Beijing, China.
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
keywords: blood-brain barrier; ischemic stroke; matrix metalloproteinases; remote ischemic perconditioning; tight junction