PMID- 25669912
OWN - NLM
STAT- MEDLINE
DCOM- 20150810
LR  - 20181113
IS  - 1559-7016 (Electronic)
IS  - 0271-678X (Print)
IS  - 0271-678X (Linking)
VI  - 35
IP  - 6
DP  - 2015 Jun
TI  - Dabigatran abrogates brain endothelial cell permeability in response to thrombin.
PG  - 985-92
LID - 10.1038/jcbfm.2015.9 [doi]
AB  - Atrial fibrillation (AF) increases the risk and severity of thromboembolic 
      stroke. Generally, antithrombotic agents increase the hemorrhagic risk of 
      thromboembolic stroke. However, significant reductions in thromboembolism and 
      intracerebral hemorrhage have been shown with the antithrombin dabigatran 
      compared with warfarin. As thrombin has been implicated in microvessel injury 
      during cerebral ischemia, we hypothesized that dabigatran decreases the risk of 
      intracerebral hemorrhage by direct inhibition of the thrombin-mediated increase 
      in cerebral endothelial cell permeability. Primary murine brain endothelial cells 
      (mBECs) were exposed to murine thrombin before measuring permeability to 4-kDa 
      fluorescein isothiocyanate-dextran. Thrombin increased mBEC permeability in a 
      concentration-dependent manner, without significant endothelial cell death. 
      Pretreatment of mBECs with dabigatran completely abrogated the effect of thrombin 
      on permeability. Neither the expressions of the endothelial cell beta1-integrins nor 
      the tight junction protein claudin-5 were affected by thrombin exposure. 
      Oxygen-glucose deprivation (OGD) also increased permeability; this effect was 
      abrogated by treatment with dabigatran, as was the additive effect of thrombin 
      and OGD on permeability. Taken together, these results indicate that dabigatran 
      could contribute to a lower risk of intracerebral hemorrhage during 
      embolism-associated ischemia from AF by protection of the microvessel 
      permeability barrier from local thrombin challenge.
FAU - Hawkins, Brian Thomas
AU  - Hawkins BT
AD  - Department of Medicine (Hematology), Division of Hematology, Seattle, Washington, 
      USA.
FAU - Gu, Yu-Huan
AU  - Gu YH
AD  - Department of Medicine (Hematology), Division of Hematology, Seattle, Washington, 
      USA.
FAU - Izawa, Yoshikane
AU  - Izawa Y
AD  - Department of Medicine (Hematology), Division of Hematology, Seattle, Washington, 
      USA.
FAU - del Zoppo, Gregory John
AU  - del Zoppo GJ
AD  - 1] Department of Medicine (Hematology), Division of Hematology, Seattle, 
      Washington, USA [2] Department of Neurology, University of Washington School of 
      Medicine, Seattle, Washington, USA.
LA  - eng
GR  - R01 NS038710/NS/NINDS NIH HHS/United States
GR  - R37 NS038710/NS/NINDS NIH HHS/United States
GR  - R01 NS053716/NS/NINDS NIH HHS/United States
GR  - NS 053716/NS/NINDS NIH HHS/United States
GR  - NS 038710/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150211
PL  - United States
TA  - J Cereb Blood Flow Metab
JT  - Journal of cerebral blood flow and metabolism : official journal of the 
      International Society of Cerebral Blood Flow and Metabolism
JID - 8112566
RN  - 0 (Antithrombins)
RN  - 0 (Benzimidazoles)
RN  - 0 (Claudin-5)
RN  - 0 (Integrin beta1)
RN  - 11P2JDE17B (beta-Alanine)
RN  - EC 3.4.21.5 (Thrombin)
RN  - I0VM4M70GC (Dabigatran)
RN  - IY9XDZ35W2 (Glucose)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Antithrombins/*pharmacology
MH  - Benzimidazoles/*pharmacology
MH  - Brain/*cytology/drug effects/metabolism
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Claudin-5/analysis
MH  - Dabigatran
MH  - Endothelial Cells/cytology/*drug effects/metabolism
MH  - Glucose/metabolism
MH  - Integrin beta1/analysis
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Oxygen/metabolism
MH  - Permeability/*drug effects
MH  - Thrombin/*metabolism
MH  - beta-Alanine/*analogs & derivatives/pharmacology
PMC - PMC4640263
EDAT- 2015/02/12 06:00
MHDA- 2015/08/11 06:00
PMCR- 2016/06/01
CRDT- 2015/02/12 06:00
PHST- 2014/08/12 00:00 [received]
PHST- 2014/12/07 00:00 [revised]
PHST- 2014/12/09 00:00 [accepted]
PHST- 2015/02/12 06:00 [entrez]
PHST- 2015/02/12 06:00 [pubmed]
PHST- 2015/08/11 06:00 [medline]
PHST- 2016/06/01 00:00 [pmc-release]
AID - jcbfm20159 [pii]
AID - 10.1038/jcbfm.2015.9 [doi]
PST - ppublish
SO  - J Cereb Blood Flow Metab. 2015 Jun;35(6):985-92. doi: 10.1038/jcbfm.2015.9. Epub 
      2015 Feb 11.