title: Opening of the blood-brain barrier before cerebral pathology in mild hyperhomocysteinemia.
abstract: Hyperhomocysteinemia (HHcy) is a risk factor for cognitive impairment. The purpose of this study was to determine the temporal pattern of cerebral pathology in a mouse model of mild HHcy, because understanding this time course provides the basis for understanding the mechanisms involved. C57Bl/6 mice with heterozygous deletion cystathionine β-synthase (cbs (+/-); Het) were used as a model of mild HHcy along with their wild-type littermates (cbs (+/+); WT). Mice were 'young' (5.3±0.2 months of age) and 'old' (16.6±0.9 months of age). Blood-brain barrier (BBB) permeability was quantified from Evans blue and sodium fluorescein extravasation. Microvascular architecture was assessed by z-stack confocal microscopy. Leukoaraiosis was measured from Luxol fast blue stained slides of paraffin brain sections. Inflammation was quantified using standard antibody-based immunohistochemical techniques. Cognitive function was assessed using the Morris water maze. BBB permeability was significantly greater in Het vs. WT mice at all ages (p<0.05). There were no differences in microvascular architecture among the groups. Compared with all other groups, old Het mice had significantly greater leukoaraiosis, inflammation in the fornix, and cognitive impairment (p<0.05). In mild HHcy, increased permeability of the BBB precedes the onset of cerebral pathology. This new paradigm may play a role in the progression of disease in HHcy.
authors.affiliation: Department of Biological Sciences, Idaho State University, Pocatello, Idaho, United States of America.
authors.forename: Bryce C
authors.initials: BC
authors.lastname: Rhodehouse
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Mayo
authors.forename: Richard S
authors.initials: RS
authors.lastname: Beard
authors.forename: Cheng-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Bearden
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology* / Q000503:physiopathology; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005070:Evans Blue / Q000737:chemistry; D020138:Hyperhomocysteinemia / Q000473:pathology / Q000503:physiopathology*; D049292:Leukoaraiosis / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal
chemical_list: D005070:Evans Blue; D003541:Cystathionine beta-Synthase