Article
Hyperhomocysteinemia Increases Permeability of the Blood-Brain Barrier by NMDA Receptor-Dependent Regulation of Adherens and Tight Junctions
Blood
(2011)
Abstract
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 β-catenin at the membrane. Moreover, Hcy caused nuclear translocation of β-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.
Disciplines
Publication Date
August 18, 2011
DOI
10.1182/blood-2011-02-338269
Publisher Statement
This document was originally published in Blood by the American Society of Hematology. Copyright restrictions may apply. doi: 10.1182/blood-2011-02-338269
Citation Information
Richard S. Beard, Jason J. Reynolds and Shawn E. Bearden. "Hyperhomocysteinemia Increases Permeability of the Blood-Brain Barrier by NMDA Receptor-Dependent Regulation of Adherens and Tight Junctions" Blood Vol. 118 Iss. 7 (2011) p. 2007 - 2014 Available at: http://works.bepress.com/richard-beard/22/