title: Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein.
abstract: Owing to the frequent incidence of blast-induced traumatic brain injury (bTBI) in recent military conflicts, there is an urgent need to develop effective therapies for bTBI-related pathologies. Blood-brain barrier (BBB) breakdown has been reported to occur after primary blast exposure, making restoration of BBB function and integrity a promising therapeutic target. We tested the hypothesis that treatment with dexamethasone (DEX) after primary blast injury potentiates recovery of an in vitro BBB model consisting of mouse brain endothelial cells (bEnd.3). DEX treatment resulted in complete recovery of transendothelial electrical resistance and hydraulic conductivity 1 day after injury, compared with 3 days for vehicle-treated injured cultures. Administration of RU486 (mifepristone) inhibited effects of DEX, confirming that barrier restoration was mediated by glucocorticoid receptor signaling. Potentiated recovery with DEX treatment was accompanied by stronger zonula occludens (ZO)-1 tight junction immunostaining and expression, suggesting that increased ZO-1 expression was a structural correlate to BBB recovery after blast. Interestingly, augmented ZO-1 protein expression was associated with specific upregulation of the α(+) isoform but not the α(-) isoform. This is the first study to provide a mechanistic basis for potentiated functional recovery of an in vitro BBB model because of glucocorticoid treatment after primary blast injury.
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, New York, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Hue
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, New York, USA.
authors.forename: Frances S
authors.initials: FS
authors.lastname: Cho
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, New York, USA.
authors.forename: Siqi
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.
authors.forename: Cameron R
authors.initials: CR
authors.lastname: Dale Bass
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
authors.affiliation: Department of Biomedical Engineering, Columbia University, New York, New York, USA.
authors.forename: Barclay
authors.initials: B
authors.lastname: Morrison
mesh_terms: D000818:Animals; D001753:Blast Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D002460:Cell Line; D003907:Dexamethasone / Q000627:therapeutic use*; D005938:Glucocorticoids / Q000627:therapeutic use*; D051379:Mice; D062826:Zonula Occludens-1 Protein / Q000032:analysis / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D062826:Zonula Occludens-1 Protein; D003907:Dexamethasone