Abstract
BACKGROUND: Cerebral edema is a consequential outcome of traumatic brain injury (TBI) and may lead to intracranial hypertension, necessitating urgent medical attention. One of the primary causes of cerebral edema is microvascular hyperpermeability, characterized by excessive leakage of intravascular fluid and proteins via blood-brain barrier (BBB) dysregulation. Prolonged activation of reactive oxygen species (ROS) formation and inflammatory pathways due to BBB hyperpermeability results in poor patient outcomes. The primary goal of this study was to ascertain if quercetin, a bioflavonoid plant pigment, would protect against BBB breakdown and hyperpermeability in the acute context following TBI. METHODS: We used a mixed in vitro and in vivo model to test the effects of quercetin pretreatment on endothelial cell tight junctions in murine models of TBI and stress-induced hyperpermeability. Hydrogen peroxide (H(2)O(2)), a key contributor of secondary injuries following TBI, was used as an inducer of oxidative stress in cerebral endothelial cells in vitro. BBB tight junction/cytoskeletal integrity was assessed using immunofluorescence of junctional proteins zonula occludens-1, β-catenin, and vascular endothelial-cadherin, alongside filamentous actin labeling and a monolayer permeability assay. Intracellular ROS and H(2)O(2) levels were determined using fluorescent probes. In vivo experiments consisted of intravital microscopy of brain pial vasculature in a mouse model of TBI. RESULTS: The results demonstrate that quercetin (100 μM; 1 h) attenuated H(2)O(2) (100 μM; 2 h)-induced monolayer hyperpermeability and ROS formation significantly and decreased the loss of tight junction and cytoskeletal integrity. Quercetin treatment (50 mg/kg) after injury decreased TBI-induced vascular hyperpermeability significantly compared to sham. These results indicate that quercetin provides BBB protection by decreasing oxidative stress-induced loss of tight junction/cytoskeletal integrity, ultimately resulting in decreased microvascular hyperpermeability. CONCLUSIONS: The data suggest that quercetin may be a viable therapeutic option for preventing or managing cerebral oedema acutely following TBI.