Elevated Hcy increases cerebral microvascular permeability, which is rescued by NMDAr inhibition with memantine. (A) Brain/serum distribution ratio of tracer (NaFl) injected into the peritoneum 2 hours before flushing blood from the vasculature and brain collection. Values were calculated as relative units of brain NaFl to serum NaFl per gram brain mass (“BBB permeability assay”) and are shown here normalized to the basal condition (WT drinking water). (B) Endogenous IgG was quantified by Western blot in brain homogenates after flushing of the vasculature. Brains of hyperhomocysteinemic mice (cbs^+/−) were significantly more permeable to IgG, which was rescued with 2 weeks of NMDAr inhibition using memantine (Mem). (C) In vitro, brain microvascular ECs (bEnd.3 cells) were significantly more permeable (flux of NaFl over 2 hours) after Hcy treatment (20μM) for 3 days, which was inhibited with concomitant antagonism of the NMDAr using memantine (Mem).