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Protection of Blood-Brain Barrier Integrity by Quercetin
Antonia Yeager, Ryan Parkinson, Chinchusha Anasooya Shaji, Himakarnika Alluri, Katie Wiggins-Dohlvik, Kevin Paul Varghese, Madhava R. Beeram, Mathew L. Davis, Binu Tharakan

The contribution of brain edema in cases of traumatic brain injury (TBI) remains a critical problem in pediatric head trauma patients. Microvascular hyperpermeability, the excessive leakage of fluid and proteins from the intravascular space to the interstitium that occurs at the level of the blood-brain barrier (BBB) is a major contributing factor to this edema formation. At a cellular level, tight junction proteins (TJPs) such as zonula occludens-1 (ZO-1) regulate the functions of the BBB. In addition to this, recent studies demonstrate that, the adherens junction protein β-catenin, is key to BBB integrity in the developing brain. Our objective was to test if quercetin a flavonoid would protect the BBB against oxidative stress-induced hyperpermeability and to understand the underlying mechanisms. Rat brain microvascular endothelial cells grown as monolayers on Transwell inserts or chamber slides were exposed to quercetin prior to induction of oxidative stress by hydrogen peroxide (H2O2). Monolayer permeability was studied using FITC-dextran assay. Tight junction/adherens integrity was studied by immunofluorescence of ZO-1, β-catenin and VE-cadherin. The cytoskeletal integrity was studied using rhodamine phalloidin staining of f-actin. Our results show that acute H2O2 (100 µM; 2 hours)-induced monolayer hyperpermeability was attenuated by quercetin (100 µM; 1 hour; (p<0.05). Quercetin protected H2O2-induced loss of ZO-1, β-catenin and VE-cadherin and decreased f-actin stress fiber formation. In conclusion, quercetin protects the BBB against oxidative stress-induced hyperpermeability via enhancement of tight/adherens junction proteins in vitro. This data contribute to better understanding the mechanisms that regular cerebral edema and may contribute to development of future therapies.


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