• Winfried Neuhaus, Carola Y Förster, Christian Wunder, Serge C Thal, Eva-Verena Schaible, David Scheffer, and Moritz Brandstetter.
• Department of Anesthesiology, Medical Center of Johannes Gutenberg-University, Mainz, Germany. thal@uni-mainz.de
• Crit. Care Med.. 2013 May 1;41(5):1305-15.

ObjectivesTo 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.DesignControlled animal study.SettingUniversity research laboratory.SubjectsMale C57Bl/6N mice.InterventionsMechanical brain lesion by controlled cortical impact.Measurements And Main ResultsOur 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.ConclusionsThe 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.

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