Prolonged Blood-Brain Barrier Injury Occurs After Experimental Intracerebral Hemorrhage and Is Not Acutely Associated wi
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ORIGINAL ARTICLE
Prolonged Blood-Brain Barrier Injury Occurs After Experimental Intracerebral Hemorrhage and Is Not Acutely Associated with Additional Bleeding Colby A. Nadeau 1 & Kristen Dietrich 2 & Cassandra M. Wilkinson 1 & Andrew M. Crawford 3 & Graham N. George 3,4 & Helen K. Nichol 5 & Frederick Colbourne 1,2 Received: 6 February 2018 / Revised: 7 May 2018 / Accepted: 4 June 2018 # The Author(s) 2018
Abstract Intracerebral hemorrhage (ICH) causes blood-brain barrier (BBB) damage along with altered element levels in the brain. BBB permeability was quantified at 3, 7, and 14 days with Evans Blue dye after collagenase-induced ICH in rat. At peak permeability (day 3), a gadolinium (Gd)-based contrast agent was injected to further characterize BBB disruption, and X-ray fluorescence imaging (XFI) was used to map Gd, Fe, Cl, and other elements. XFI revealed that Ca, Cl, Gd, and Fe concentrations were significantly elevated, whereas K was significantly decreased. Therefore, using Gd-XFI, we co-determined BBB dysfunction with alterations in the metallome, including those that contribute to cell death and functional outcome. Warfarin was administered 3 days post-ICH to investigate whether additional or new bleeding occurs during peak BBB dysfunction, and hematoma volume was assessed on day 4. Warfarin administration prolonged bleeding time after a peripheral cut-induced bleed, but warfarin did not worsen hematoma volume. Accordingly, extensive BBB leakage occurred after ICH, but did not appear to affect total hematoma size. Keywords Blood-brain barrier . Gadolinium extravasation . Ion dyshomeostasis . Intracerebral hemorrhage . X-ray fluorescence imaging
Introduction Intracerebral hemorrhage (ICH), characterized by one or more vessels rupturing in the parenchyma, has a > 40% mortality rate. Currently, ICH accounts for 10–15% of all strokes and often leads to lifelong disabilities in its survivors [1].
* Frederick Colbourne [email protected] 1
Department of Psychology, University of Alberta, P217 Biological Sciences Building, Edmonton, Alberta T6G 2E9, Canada
2
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada
3
Molecular and Environmental Sciences Group, Department of Geological Sciences, University of Saskatchewan, Saskatoon, Canada
4
Department of Chemistry, University of Saskatchewan, Saskatoon, Canada
5
Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, Canada
Anticoagulants such as warfarin contribute to ~ 20% of hemo r r h ag e c a s e s a nd m a y t r a ns f or m as y m p t o m a t i c microhemorrhages (cerebral microbleeds; CMBs) into symptomatic ICH [2, 3]. Newer anticoagulants do not increase the risk of ICH but negatively impact outcome if ICH occurs [4]. Multiphasic blood-brain barrier (BBB) dysfunction is observed post-ICH. Acute BBB dysfunction occurs at ictus, and delayed BBB opening is related to secondary injury (e.g., inflammation) and repair (e.g., angiogenesis) processes [5, 6]. Increased BBB permeability in the region sur
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