Hyperhomocysteinemia increases permeability of the blood-brain barrier by NMDA receptor-dependent regulation of adherens and tight junctions

摘要: Hyperhomocysteinemia (HHcy) increases permeability of the blood-brain barrier, but mechanisms are undetermined. Homocysteine (Hcy) is an agonist neuronal N-methyl-D-aspartate receptor (NMDAr). We tested hypothesis that HHcy disrupts barrier by NMDAr-dependent mechanism in endothelium. In brain microvascular endothelial cells, there was no change expression adherens junction protein VE-cadherin with Hcy treatment, a significant decrease amount β-catenin at membrane. Moreover, caused nuclear translocation and attachment to promoter for tight claudin-5, concomitant reduction claudin-5 expression. Using murine model (cbs+/−), treatment 2 weeks NMDAr antagonist (memantine) rescued cerebrovascular both exogenous sodium fluorescein endogenous IgG. Memantine had effect on these parameters wild-type littermates. The same results were obtained using vitro cells. These data provide first evidence required Hcy-mediated permeability. Modulating cerebral activity may present novel therapeutic target diseases associated opening HHcy, such as stroke dementia.