title: Vitexin reduces hypoxia-ischemia neonatal brain injury by the inhibition of HIF-1alpha in a rat pup model.
abstract: Previous studies have demonstrated that the early suppression of HIF-1α after hypoxia-ischemia (HI) injury provides neuroprotection. Vitexin (5, 7, 4-trihydroxyflavone-8-glucoside), an HIF-1α inhibitor, is a c-glycosylated flavone that has been identified in medicinal plants. Therefore, we hypothesized that treatment with vitexin would protect against HI brain injury. Newborn rat pups were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia (8% O2 at 37 °C). Vitexin (30, 45 or 60 mg/kg) was administered intraperitoneally at 5 min or 3 h after HI. Vitexin, administered 5 min after HI, was neuroprotective as seen by decreased infarct volume evaluated at 48 h post-HI. This neuroprotection was removed when vitexin was administered 3 h after HI. Neuronal cell death, blood-brain barrier (BBB) integrity, brain edema, HIF-1α and VEGF protein levels were evaluated using a combination of Nissl staining, IgG staining, brain water content, immunohistochemistry and Western blot at 24 and 48 h after HI. The long-term effects of vitexin were evaluated by brain atrophy measurement, Nissl staining and neurobehavioral tests. Vitexin (45 mg/kg) ameliorated brain edema, BBB disruption and neuronal cell death; Upregulation of HIF-1α by dimethyloxalylglycine (DMOG) increased the BBB permeability and brain edema compared to HI alone. Vitexin attenuated the increase in HIF-1α and VEGF. Vitexin also had long-term effects of protecting against the loss of ipsilateral brain and improveing neurobehavioral outcomes. In conclusion, our data indicate early HIF-1α inhibition with vitexin provides both acute and long-term neuroprotection in the developing brain after neonatal HI injury.
authors.affiliation: Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Min
authors.affiliation: Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
authors.forename: Jiang-Jian
authors.initials: JJ
authors.lastname: Hu
authors.affiliation: Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
authors.forename: Miao
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Surgery, College of Medicine, Texas A&M Health Science Center, Neuroscience Institute, Scott & White Hospital, & Central Texas Veterans Health Care System, Temple, TX, USA.
authors.forename: Russell M
authors.initials: RM
authors.lastname: Sanchez
authors.affiliation: Department of Pathophysiology, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
authors.forename: Wen-Xian
authors.initials: WX
authors.lastname: Huang
authors.affiliation: Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
authors.forename: Yu-Qiang
authors.initials: YQ
authors.lastname: Liu
authors.affiliation: Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
authors.forename: Najeeb Bassam
authors.initials: NB
authors.lastname: Bsoul
authors.affiliation: Department of Pathophysiology, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
authors.forename: Song
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pathophysiology, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
authors.forename: Wan-Hong
authors.initials: WH
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, School of Basic Medical Sciences, Wuhan University, Wuhan, China. Electronic address: hexiaohua@whu.edu.cn.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: He
authors.affiliation: Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disorder, School of Basic Medical Sciences, Wuhan University, Wuhan, China. Electronic address: pengbiwen@whu.edu.cn.
authors.forename: Bi-Wen
authors.initials: BW
authors.lastname: Peng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D047310:Apigenin / Q000737:chemistry / Q000494:pharmacology*; D001284:Atrophy / Q000188:drug therapy / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D047310:Apigenin; C032731:vitexin
keywords: Hypoxia-inducible factor; Hypoxia–ischemia; Neonatal rat; Vitexin