Abstract
Recent studies have implicated 20-HETE as a vasoconstrictive mediator in trauma, the purpose of this study was to determine whether administration of HET0016, the 20-HETE inhibitor, could protect neurons from trauma and the effect of HET0016 on the blood–brain barrier (BBB) and brain edema in experimental traumatic brain injury (TBI). Rat models with TBI were established. Brain edema was measured according to the wet and dry weight method at 3, 24, and 72 h after injury. The BBB permeability was quantified by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Superoxide production, the activity of superoxide dismutase (SOD) and total antioxidative capability (T-AOC) in traumatic brain tissues were also measured. Western blot analysis was used to analyze the expression of the occludin, ZO-1, Matrix metalloproteinase-9 (MMP-9), and c-Jun N-terminal protein kinase (JNK) pathways. At 24 and 72 h after administration of HET0016 following TBI, the BBB permeability and brain edema decreased. The decrease in superoxide production and the increase in the activity of SOD and T-AOC were measured in this study. Western blot analysis showed that the expression of MMP-9 and JNK pathways was suppressed, but the expression of ZO-1 and occludin was increased. These results suggest that the administration of HET0016 could protect the BBB function and decrease brain edema after experimental traumatic injury by suppressing the expression of MMP-9 and activating the expression of tight junction proteins via suppressing the JNK pathway and oxidative stress.
Highlights
Traumatic brain injury (TBI) induces arachidonic acid (AA) release from cell membranes (Birnie et al, 2013)
Cytochrome P450 (CYP) enzymes, especially four different CYP4A isozymes, can catalyze the ω-hydroxylation of AA to 20-hydroxyeicosatetraenoic acid (20-HETE) (Johnson et al, 2015). 20-HETE has long been recognized as a potent vasoconstrictor of the microvasculature (Hall et al, 2014) in cerebral circulation, and several studies suggested that 20-HETE has important biological and pathological functions in the regulation of vasculature, cerebral blood flow (CBF), cellular proliferation, and the inflammation reaction
Western blot analysis revealed that the expression of ZO-1(Figures 5A,B) and occludin (Figures 5C,D) markedly diminished in the TBI group compared with the sham group at Expression of Matrix metalloproteinase-9 (MMP-9)
Summary
Traumatic brain injury (TBI) induces arachidonic acid (AA) release from cell membranes (Birnie et al, 2013). 20-HETE increases the vascular production of reactive oxygen species (ROS), promotes NF-κB activation in cerebromicrovascular endothelial cells, and deteriorates inflammation (Toth et al, 2013). ROS, which are considered part of the secondary injury, are implicated in the major pathology of diverse acute and chronic brain injuries (Wei et al, 2012). ROS can cause blood–brain barrier (BBB) disruption and increase the cerebral vascular permeability, leading to the formation of brain edema (Wei et al, 2012)
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