title: Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions.
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.
authors.affiliation: Department of Biological Sciences, Idaho State University, Pocatello, ID 83209-8007, USA.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Beard
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Reynolds
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Bearden
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D062507:Claudin-5; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D019108:Tight Junctions / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D062507:Claudin-5; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D051176:beta Catenin; D000099152:Cadherin 5; C491511:Cldn5 protein, mouse