title: Omega-3 polyunsaturated fatty acids mitigate blood-brain barrier disruption after hypoxic-ischemic brain injury.
abstract: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been shown to protect the neonatal brain against hypoxic/ischemic (H/I) injury. However, the mechanism of n-3 PUFA-afforded neuroprotection is not well understood. One major determinant of H/I vulnerability is the permeability of the blood-brain barrier (BBB). Therefore, we examined the effects of n-3 PUFAs on BBB integrity after neonatal H/I. Female rats were fed a diet with or without n-3 PUFA enrichment from day 2 of pregnancy to 14days after parturition. H/I was introduced in 7day-old offspring. We observed relatively rapid BBB penetration of the small molecule cadaverine (640Da) at 4h post-H/I and a delayed penetration of larger dextrans (3kD-40kD) 24-48h after injury. Surprisingly, the neonatal BBB was impermeable to Evans Blue or 70kD dextran leakage for up to 48h post-H/I, despite evidence of IgG extravasation at this time. As expected, n-3 PUFAs ameliorated H/I-induced BBB damage, as shown by reductions in tracer efflux and IgG extravasation, preservation of BBB ultrastructure, and enhanced tight junction protein expression. Furthermore, n-3 PUFAs prevented the elevation in matrix metalloproteinase (MMP) activity in the brain and blood after H/I. Thus, n-3 PUFAs may protect neonates against BBB damage by blunting MMPs activation after H/I.
authors.affiliation: State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Department of Neurology of Huashan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Mu
authors.affiliation: Center of Cerebrovascular Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.affiliation: Center of Cerebrovascular Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Yejie
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282, USA.
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.affiliation: State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Department of Neurology of Huashan Hospital, Fudan University, Shanghai 200032, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA 15261, USA. Electronic address: chenj2@upmc.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences, Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; Center of Cerebrovascular Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: yqgao@shmu.edu.cn.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D015525:Fatty Acids, Omega-3 / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000378:metabolism*; D017207:Rats, Sprague-Dawley
chemical_list: D015525:Fatty Acids, Omega-3
keywords: Blood brain barrier; Hypoxia/ischemia; MMP-2; MMP-9; Tight junction