title: Inhibition of proteasomal glucocorticoid receptor degradation restores dexamethasone-mediated stabilization of the blood-brain barrier after traumatic brain injury.
abstract: OBJECTIVE
  To establish the molecular background for glucocorticoid insensitivity, that is, failure to reduce edema formation and to protect blood-brain barrier integrity after acute traumatic brain injury.
  
  
  METHODS
  Controlled animal study.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Male C57Bl/6N mice.
  
  
  METHODS
  Mechanical brain lesion by controlled cortical impact.
  
  
  RESULTS
  Our study demonstrates that 1) proteasomal glucocorticoid receptor degradation is established in brain endothelial cells after traumatic brain injury as a form of posttranslational glucocorticoid receptor modification; 2) inhibition of the proteasomal degradation pathway with bortezomib (0.2 mg/kg) in combination with the glucocorticoid dexamethasone (10 mg/kg) by subcutaneous injection 30 minutes postinjury restores levels of barrier sealing glucocorticoid receptor target occludin in brain endothelial cells, improves blood-brain barrier integrity, reduces edema formation, and limits neuronal damage after brain trauma.
  
  
  CONCLUSIONS
  The results indicate that the stabilizing effect of glucocorticoids on the blood-brain barrier is hampered after cerebral lesions by proteasomal glucocorticoid receptor degradation in brain endothelial cells and restored by inhibition of proteasomal degradation pathways. The results provide underlying mechanisms for the clinically observed inefficacy of glucocorticoids. The novel combined treatment strategy might help to attenuate trauma-induced brain edema formation and neuronal damage as secondary effects of brain trauma.
authors.affiliation: Department of Anesthesiology, Medical Center of Johannes Gutenberg-University, Mainz, Germany. thal@uni-mainz.de
authors.forename: Serge C
authors.initials: SC
authors.lastname: Thal
authors.forename: Eva-Verena
authors.initials: EV
authors.lastname: Schaible
authors.forename: Winfried
authors.initials: W
authors.lastname: Neuhaus
authors.forename: David
authors.initials: D
authors.lastname: Scheffer
authors.forename: Moritz
authors.initials: M
authors.lastname: Brandstetter
authors.forename: Kristin
authors.initials: K
authors.lastname: Engelhard
authors.forename: Christian
authors.initials: C
authors.lastname: Wunder
authors.forename: Carola Y
authors.initials: CY
authors.lastname: Förster
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D001929:Brain Edema / Q000188:drug therapy / Q000517:prevention & control; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015999:Multivariate Analysis; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism; D012016:Reference Values; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D000069286:Bortezomib; D003907:Dexamethasone; D046988:Proteasome Endopeptidase Complex