Cysteinyl leukotriene receptor type 1 antagonist montelukast protects against injury of blood-brain barrier.

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 1β (IL-1β), 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.