ABSTRACT
The blood-brain barrier (BBB) is formed by tightly connected cerebrovascular endothelial cells. Injury of human brain endothelial cells can cause disruption of the BBB and severe injury to brain tissue. Signals mediated cysteinyl leukotrienes (cysLTs) and their receptors are involved in a variety of pathological conditions. In the current study, our results show that oxygen glucose-deprivation/reoxygenation (OGD/R) induced the expression of leukotriene receptor type 1 (cysLT1R) in brain endothelial cells. Blockage of cysLT1R by its specific antagonist montelukast suppressed OGD/R-induced altered permeability of the human brain endothelial cell (EC) monolayer. Mechanistically, montelukast treatment reversed OGD/R-induced reduction of the tight junction proteins occludin and zonula occludens-1 (ZO-1). Montelukast also ameliorated OGD/R-induced reduction of inhibitors of matrix metalloproteinases (TIMPs), such as TIMP-1 and TIMP-2. On the other hand, montelukast suppressed the expression and production of matrix metalloproteinases (MMPs) and cytokines including MMP-2, MMP-9, interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6). Using a murine middle cerebral artery occlusion brain injury model, we demonstrated that the administration of montelukast improved the surgery-induced brain injury and protected against disruption of brain endothelial junction proteins such as occludin and ZO-1. Collectively, our data suggest that montelukast might confer protective roles against injury in brain endothelial cells.
Subject(s)
Acetates/pharmacology , Blood-Brain Barrier/drug effects , Brain Ischemia/drug therapy , Leukotriene Antagonists/pharmacology , Quinolines/pharmacology , Receptors, Leukotriene/metabolism , Animals , Blood-Brain Barrier/metabolism , Brain/drug effects , Brain/metabolism , Brain Ischemia/metabolism , Cell Line , Cyclopropanes , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Sulfides , Tissue Inhibitor of Metalloproteinase-1/metabolism , Tissue Inhibitor of Metalloproteinase-2/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Hypothermia is an effective neuroprotective treatment for brain injury caused by intracerebral hemorrhage (ICH). It is reported to reduce brain edema and neuronal cell death. Thrombin, a coagulation protease released from blood clots, is critical in brain edema formation following ICH. Protease activated receptor1 (PAR1), matrix metalloproteinase9 (MMP9) and aquaporin 4 (AQP4) are edemaassociated mediators that have been implicated in ICH pathology. In the present study, thrombin was used to induce brain edema in adult male SpragueDawley rats. Differences between a focal mild hypothermic group (33±0.5ËC) and a normothermic group (37ËC) were investigated. Following hypothermia, brain water content and bloodbrain barrier (BBB) disruption was assessed at 6, 24 and 48 h and subsequently at 3, 5 and 7 days. At the same time, the mRNA and protein expression of PAR1, MMP9 and AQP4 were also determined. It was identified that brain water content and BBB disruption increased at 6 h and reached a maximal level at 24 h in the normothermic group. The mRNA and protein expression levels of PAR1, MMP9 and AQP4 started to increase at 24 h and reached a maximal level at 48 h. Focal mild hypothermia tended to significantly reduce brain water content, BBB disruption and PAR1, MMP9 and AQP expression at 24 and 48 h. The present data suggest that focal mild hypothermia is an effective treatment for edema formation through moderation of the mRNA and protein expression of PAR1, MMP9 and AQP4.
