Inhibition of proteasomal glucocorticoid receptor degradation restores dexamethasone-mediated stabilization of the blood-brain barrier after traumatic brain injury

摘要

OBJECTIVES: 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. DESIGN: Controlled animal study. SETTING: University research laboratory. SUBJECTS: Male C57Bl/6N mice. INTERVENTIONS: Mechanical brain lesion by controlled cortical impact. MEASUREMENTS AND MAIN 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.