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Reena Bapputty, Ramaprasad Talahalli, Rose Gubitosi-Klug; Montelukast modulates diabetes-induced inflammatory cascades and endothelial cell dysfunction. Invest. Ophthalmol. Vis. Sci. 2020;61(7):746.
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In the mouse model of diabetes, leukocyte-derived pro-inflammatory mediators have been implicated in retinal microvascular endothelial cell dysfunction and death. In the current study we investigated the effect of montelukast, a leukotriene receptor antagonist, on 1) gene expression of inflammatory cascades in leukocytes and apoptotic cascades in the retina from mice and 2) tight junction proteins in cultured mouse retinal microvascular endothelial cells (mREC).
Montelukast (5mg/kg body weight) was administered to mice immediately following streptozotocin-induction of diabetes. Gene expression profiles of inflammatory leukotrienes and cytokines in leukocytes were quantified by real-time PCR at 12-weeks of diabetes duration and retinal caspase 3 at 28-weeks of diabetes duration. Tight junction proteins, occludin, ZO-1, and claudin-5 were quantified by western blotting of lysates from mouse retinal microvascular endothelial cells cultured in high glucose (25 mM).
Compared to leukocytes from non-diabetic mice, diabetes induced a 3-fold increase in leukotriene C4 receptor, CysLT1, gene expression and a 5-fold increase in cytokine receptor, CCR2, in leukocytes from diabetic mice. Montelukast treatment significantly inhibited this diabetes-induced CysLT1 gene expression by 35% (p=0.03) and CCR2 by 41% (p=0.03). Montelukast administration also resulted in a significant decrease in diabetes-induced caspase 3 level (p=0.001) in the retina. In vitro experiments showed that montelukast preserved occludin levels (p=0.03) in mouse retinal endothelial cells, preventing the diabetes-induced loss of this tight junction protein.
Gene expressions studies along with in vivo and in vitro studies corroborate that montelukast dampens inflammatory changes in leukocytes early in diabetes which correspond with long-term maintenance of endothelial cell tight junctions and viability.
This is a 2020 ARVO Annual Meeting abstract.
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