Opening of the blood-brain barrier before cerebral pathology in mild hyperhomocysteinemia

• Published in: PloS one Vol. 8; no. 5; p. e63951
• Main Authors: Rhodehouse, Bryce C, Mayo, Jamie N, Beard, Jr, Richard S, Chen, Cheng-Hung, Bearden, Shawn E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.05.2013; Public Library of Science (PLoS)
• Subjects: Age; Analysis; Animal cognition; Animals; Apoptosis; Architecture; Autophagy; Biology; Blood-brain barrier; Blood-Brain Barrier - pathology; Blood-Brain Barrier - physiopathology; Brain; Brain - pathology; Brain - physiopathology; Cell death; Cognitive ability; Confocal microscopy; Cystathionine beta-Synthase - genetics; Cystathionine beta-Synthase - metabolism; Disease Models, Animal; Enzymes; Evans Blue - chemistry; Extravasation; Fluorescein; Fornix; Homocysteine; House mouse; Hyperhomocysteinemia; Hyperhomocysteinemia - pathology; Hyperhomocysteinemia - physiopathology; Hypertension; Impairment; Laboratory animals; Leukoaraiosis; Leukoaraiosis - pathology; Male; Medicine; Membrane permeability; Mice; Mice, Inbred C57BL; Microscopy; Microscopy, Confocal; Microvasculature; Mutation; Paraffin; Pathology; Permeability; Risk factors; Rodents; Sodium; Stroke; Systematic review; Vitamin deficiency; United States > US; Idaho
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0063951

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.