PMID- 21705496
OWN - NLM
STAT- MEDLINE
DCOM- 20111012
LR  - 20220316
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 118
IP  - 7
DP  - 2011 Aug 18
TI  - Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA 
      receptor-dependent regulation of adherens and tight junctions.
PG  - 2007-14
LID - 10.1182/blood-2011-02-338269 [doi]
AB  - Hyperhomocysteinemia (HHcy) increases permeability of the blood-brain barrier, 
      but the mechanisms are undetermined. Homocysteine (Hcy) is an agonist of the 
      neuronal N-methyl-D-aspartate receptor (NMDAr). We tested the hypothesis that 
      HHcy disrupts the blood-brain barrier by an NMDAr-dependent mechanism in 
      endothelium. In brain microvascular endothelial cells, there was no change in 
      expression of the adherens junction protein VE-cadherin with Hcy treatment, but 
      there was a significant decrease in the amount of beta-catenin at the membrane. 
      Moreover, Hcy caused nuclear translocation of beta-catenin and attachment to the 
      promoter for the tight junction protein claudin-5, with concomitant reduction in 
      claudin-5 expression. Using a murine model of HHcy (cbs(+/-)), treatment for 2 
      weeks with an NMDAr antagonist (memantine) rescued cerebrovascular expression of 
      claudin-5 and blood-brain barrier permeability to both exogenous sodium 
      fluorescein and endogenous IgG. Memantine had no effect on these parameters in 
      wild-type littermates. The same results were obtained using an in vitro model 
      with brain microvascular endothelial cells. These data provide the first evidence 
      that the NMDAr is required for Hcy-mediated increases in blood-brain barrier 
      permeability. Modulating cerebral microvascular NMDAr activity may present a 
      novel therapeutic target in diseases associated with opening of the blood-brain 
      barrier in HHcy, such as stroke and dementia.
FAU - Beard, Richard S Jr
AU  - Beard RS Jr
AD  - Department of Biological Sciences, Idaho State University, Pocatello, ID 
      83209-8007, USA.
FAU - Reynolds, Jason J
AU  - Reynolds JJ
FAU - Bearden, Shawn E
AU  - Bearden SE
LA  - eng
GR  - P20 RR016454/RR/NCRR NIH HHS/United States
GR  - P20 RR-016454/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110624
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antigens, CD)
RN  - 0 (Cadherins)
RN  - 0 (Claudin-5)
RN  - 0 (Cldn5 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 0 (beta Catenin)
RN  - 0 (cadherin 5)
SB  - IM
MH  - Adherens Junctions/*metabolism
MH  - Animals
MH  - Antigens, CD/metabolism
MH  - Biological Transport
MH  - Blood-Brain Barrier/*metabolism
MH  - Cadherins/metabolism
MH  - Cell Line
MH  - Claudin-5
MH  - Endothelial Cells/metabolism
MH  - Endothelium, Vascular/metabolism
MH  - Female
MH  - Gene Expression Regulation
MH  - Hyperhomocysteinemia/genetics/*metabolism
MH  - Male
MH  - Membrane Proteins/genetics
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Permeability
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Tight Junctions/*metabolism
MH  - beta Catenin/metabolism
PMC - PMC3158726
EDAT- 2011/06/28 06:00
MHDA- 2011/10/13 06:00
PMCR- 2012/08/18
CRDT- 2011/06/28 06:00
PHST- 2011/06/28 06:00 [entrez]
PHST- 2011/06/28 06:00 [pubmed]
PHST- 2011/10/13 06:00 [medline]
PHST- 2012/08/18 00:00 [pmc-release]
AID - S0006-4971(20)41116-4 [pii]
AID - 2011/338269 [pii]
AID - 10.1182/blood-2011-02-338269 [doi]
PST - ppublish
SO  - Blood. 2011 Aug 18;118(7):2007-14. doi: 10.1182/blood-2011-02-338269. Epub 2011 
      Jun 24.