QUETIAPINE PROTECTS THE BLOOD-BRAIN BARRIER IN TRAUMATIC BRAIN INJURY

Background The integrity of the blood-brain barrier (BBB) is paramount in limiting vasogenic edema following traumatic brain injury (TBI). The purpose of this study was to ascertain if quetiapine, an atypical antipsychotic commonly used in trauma/critical care for delirium, protects the BBB and attenuates hyperpermeability in TBI. Method The effect of quetiapine on hyperpermeability was examined through molecular modeling, cellular models in vitro and small animal models in vivo. Molecular docking was performed with AutoDock Vina to matrix metalloproteinase-9 (MMP-9). Rat brain microvascular endothelial cells (BMECs) were pretreated with quetiapine (20μM; 1 hour) followed by an inflammatory activator (20μg/mL chitosan; 2 hours) and compared to controls. Immunofluorescence localization for tight junction proteins zonula occludens-1 (ZO-1) and adherens junction protein β-catenin was performed. Human BMECs were grown as a monolayer and pretreated with quetiapine (20μM; 1 hour) followed by chitosan (20μg/mL; 2 hours), and transendothelial electrical resistance (TEER) was measured. C57BL/6 mice (n=5/group) underwent mild-moderate TBI (controlled cortical impactor) or sham craniotomy. The treatment group was given 10 mg/kg quetiapine intravenously 10 minutes after TBI. The difference in fluorescence intensity between intravascular and interstitium (ΔI) represented BBB hyperpermeability. An MMP-9 activity assay was performed in brain tissue from animals in the experimental groups ex vivo. Results In silico studies showed quetiapine thermodynamically-favorable binding to MMP-9. Junctional localization of ZO-1 and β-catenin showed retained integrity in quetiapine-treated cells as compared to the chitosan group in rat BMECs. Quetiapine attenuated monolayer permeability compared to chitosan group (p

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