Quetiapine protects the blood-brain barrier in traumatic brain injury

Autor: Binu Tharakan, Stanley Kurek, Chinchusha Anasooya Shaji, Bobby Darnell Robinson, Justin L. Regner, Claire L. Isbell
Rok vydání: 2018
Předmět:
Male
Models
Molecular
0301 basic medicine
Intravital Microscopy
medicine.drug_class
Traumatic brain injury
Atypical antipsychotic
Pharmacology
Critical Care and Intensive Care Medicine
Blood–brain barrier
Permeability
Tight Junctions
Mice
Quetiapine Fumarate
03 medical and health sciences
0302 clinical medicine
In vivo
Brain Injuries
Traumatic
Electric Impedance
Animals
Humans
Medicine
Computer Simulation
Cells
Cultured
beta Catenin
Chitosan
Tight junction
business.industry
Brain
Endothelial Cells
medicine.disease
Rats
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
medicine.anatomical_structure
Matrix Metalloproteinase 9
Blood-Brain Barrier
Microvessels
Zonula Occludens-1 Protein
Quetiapine
Surgery
business
030217 neurology & neurosurgery
Ex vivo
Intravital microscopy
Antipsychotic Agents
medicine.drug
Zdroj: Journal of Trauma and Acute Care Surgery. 85:968-976
ISSN: 2163-0763
2163-0755
DOI: 10.1097/ta.0000000000002011
Popis: 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. METHODS 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. Rat brain microvascular endothelial cells (BMECs) were pretreated with quetiapine (20 μM; 1 hour) followed by an inflammatory activator (20 μg/mL chitosan; 2 hours) and compared to controls. Immunofluorescence localization for tight junction proteins zonula occludens-1 and adherens junction protein β-catenin was performed. Human BMECs were grown as a monolayer and pretreated with quetiapine (20 μM; 1 hour) followed by chitosan (20 μg/mL; 2 hours), and transendothelial electrical resistance was measured. C57BL/6 mice (n = 5/group) underwent mild to 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. A matrix metalloproteinase-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 zonula occludens-1 and β-catenin showed retained integrity in quetiapine-treated cells as compared with the chitosan group in rat BMECs. Quetiapine attenuated monolayer permeability compared with chitosan group (p < 0.05) in human BMECs. In the animal studies, there was a significant decrease in BBB hyperpermeability and MMP-9 activity when compared between the TBI and TBI plus quetiapine groups (p < 0.05). CONCLUSION Quetiapine treatment may have novel anti-inflammatory properties to provide protection to the BBB by preserving tight junction integrity. LEVEL OF EVIDENCE level IV.
Databáze: OpenAIRE
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