title: Zinc contributes to acute cerebral ischemia-induced blood-brain barrier disruption.
abstract: Zinc ions are stored in synaptic vesicles and cerebral ischemia triggers their release from the terminals of neurons. Zinc accumulation in neurons has been shown to play an important role in neuronal death following ischemia. However, almost nothing is known about whether zinc is involved in ischemia-induced blood-brain barrier (BBB) disruption. Herein, we investigated the contribution of zinc to ischemia-induced acute BBB disruption and the possible molecular mechanisms using both cellular and animal models of cerebral ischemia. Zinc greatly increased BBB permeability and exacerbated the loss of tight junction proteins (Occludin and Claudin-5) in the endothelial monolayer under oxygen glucose deprivation conditions. In cerebral ischemic rats, a dramatically elevated level of zinc accumulation in microvessels themselves was observed in isolated microvessels and in situ, showing the direct interaction of zinc on ischemic microvessels. Treatment with a specific zinc chelator N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), even at 60-min post-ischemia onset, could greatly attenuate BBB permeability in the ischemic rats as measured by Evan's Blue extravasation, edema volume and magnetic resonance imaging. Furthermore, zinc accumulation in microvessels activated the superoxide/matrix metalloproteinase-9/-2 pathway, which leads to the loss of tight junction proteins (Occludin and Claudin-5) and death of endothelial cells in microvessels themselves. Our findings reveal a novel mechanism of cerebral ischemia-induced BBB damage, and implicate zinc as an effective and viable new target for reducing acute BBB damage following ischemic stroke.
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China; Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131-0001, USA.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Central Laboratory of Liaoning Medical University, Jinzhou, Liaoning, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131-0001, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Pan
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Dong
authors.affiliation: School of Chinese Medicine, University of Hong Kong, Hong Kong, Hong Kong.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131-0001, USA.
authors.forename: Yirong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Shi
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China.
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.affiliation: Cerebrovascular Diseases Research Institute, Xuanwu hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China; Department of Pharmaceutical Sciences, University of New Mexico, Albuquerque, NM 87131-0001, USA. Electronic address: kliu@salud.unm.edu.
authors.forename: Ke Jian
authors.initials: KJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology*; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D005029:Ethylenediamines / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010539:Permeability / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy / Q000473:pathology; D062725:Tight Junction Proteins / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D005029:Ethylenediamines; D062725:Tight Junction Proteins; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: Blood–brain barrier; Brain ischemia; Cell death; Matrix metalloproteinases; Microvessel; Tight junction proteins; Zinc