PMID- 23675346
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20130516
LR  - 20211021
IS  - 1663-4365 (Print)
IS  - 1663-4365 (Electronic)
IS  - 1663-4365 (Linking)
VI  - 5
DP  - 2013
TI  - Thrombin, a mediator of cerebrovascular inflammation in AD and hypoxia.
PG  - 19
LID - 10.3389/fnagi.2013.00019 [doi]
LID - 19
AB  - Considerable evidence implicates hypoxia and vascular inflammation in Alzheimer's 
      disease (AD). Thrombin, a multifunctional inflammatory mediator, is demonstrable 
      in the brains of AD patients both in the vessel walls and senile plaques. 
      Hypoxia-inducible factor 1alpha (HIF-1alpha), a key regulator of the cellular response to 
      hypoxia, is also upregulated in the vasculature of human AD brains. The objective 
      of this study is to investigate inflammatory protein expression in the 
      cerebrovasculature of transgenic AD mice and to explore the role of thrombin as a 
      mediator of cerebrovascular inflammation and oxidative stress in AD and in 
      hypoxia-induced changes in brain endothelial cells. Immunofluorescent analysis of 
      the cerebrovasculature in AD mice demonstrates significant (p < 0.01-0.001) 
      increases in thrombin, HIF-1alpha, interleukin-6 (IL-6), monocyte chemoattractant 
      protein-1 (MCP-1), matrix metalloproteinases (MMPs), and reactive oxygen species 
      (ROS) compared to controls. Administration of the thrombin inhibitor dabigatran 
      (100 mg/kg) to AD mice for 34 weeks significantly decreases expression of 
      inflammatory proteins and ROS. Exposure of cultured brain endothelial cells to 
      hypoxia for 6 h causes an upregulation of thrombin, HIF-1alpha, MCP-1, IL-6, and MMP2 
      and ROS. Treatment of endothelial cells with the dabigatran (1 nM) reduces ROS 
      generation and inflammatory protein expression (p < 0.01-0.001). The data 
      demonstrate that inhibition of thrombin in culture blocks the increase in 
      inflammatory protein expression and ROS generation evoked by hypoxia. Also, 
      administration of dabigatran to transgenic AD mice diminishes ROS levels in brain 
      and reduces cerebrovascular expression of inflammatory proteins. Taken together, 
      these results suggest that inhibiting thrombin generation could have therapeutic 
      value in AD and other disorders where hypoxia, inflammation, and oxidative stress 
      are involved.
FAU - Tripathy, Debjani
AU  - Tripathy D
AD  - Garrison Institute on Aging, Department of Neurology, Texas Tech University 
      Health Sciences Center Lubbock, TX, USA.
FAU - Sanchez, Alma
AU  - Sanchez A
FAU - Yin, Xiangling
AU  - Yin X
FAU - Luo, Jinhua
AU  - Luo J
FAU - Martinez, Joseph
AU  - Martinez J
FAU - Grammas, Paula
AU  - Grammas P
LA  - eng
GR  - R01 AG020569/AG/NIA NIH HHS/United States
GR  - R01 AG028367/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20130509
PL  - Switzerland
TA  - Front Aging Neurosci
JT  - Frontiers in aging neuroscience
JID - 101525824
PMC - PMC3648692
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - dabigatran
OT  - endothelial cells
OT  - hypoxia
OT  - neuroinflammation
OT  - thrombin
EDAT- 2013/05/16 06:00
MHDA- 2013/05/16 06:01
PMCR- 2013/01/01
CRDT- 2013/05/16 06:00
PHST- 2013/03/11 00:00 [received]
PHST- 2013/04/09 00:00 [accepted]
PHST- 2013/05/16 06:00 [entrez]
PHST- 2013/05/16 06:00 [pubmed]
PHST- 2013/05/16 06:01 [medline]
PHST- 2013/01/01 00:00 [pmc-release]
AID - 10.3389/fnagi.2013.00019 [doi]
PST - epublish
SO  - Front Aging Neurosci. 2013 May 9;5:19. doi: 10.3389/fnagi.2013.00019. eCollection 
      2013.