Purchase this article with an account.
Rose A. Gubitosi-Klug, Ramaprasad Talahalli; Leukotriene Receptor Antagonism Reduces Early Diabetic Retinopathy in the Mouse. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2214.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Chronic inflammation and oxidative stress are critical components in the pathogenic cascade leading to capillary degeneration, the hallmark feature of early diabetic retinopathy. Our prior investigations implicate the pro-inflammatory leukotrienes as key mediators of retinal inflammation and oxidative stress in the diabetic mouse. Indeed, diabetic mice genetically-deficient in leukotriene generation are protected from capillary degeneration, yet it is not known whether pharmacologic inhibition of the leukotriene cascade is therapeutically beneficial in diabetic retinopathy. In this current study, we investigated the effects of montelukast, a leukotriene receptor antagonist, on capillary degeneration in diabetic mice.
Immediately following induction of diabetes using streptozotocin, diabetic mice were administered montelukast (5mg/kg/day dissolved in drinking water). Montelukast-treated mice were compared to untreated diabetic and non-diabetic mice with regard to the following parameters 1) retinal superoxide production, 2) nuclear localization of the pro-inflammatory transcription factor NFkB (p65 subunit) in retinal cells, 3) vascular permeability, 4) serum cytokine expression, and 5) capillary degeneration.
Administration of montelukast to diabetic mice resulted in the suppression of retinal superoxide generation (p < 0.0001) and a 60% reduction in nuclear NFkB (p65 subunit) levels when compared to retinas from untreated diabetic mice. (p < 0.05) Retinal vascular permeability, as measured in vivo by retinal accumulation of perfused Evans Blue Dye, was significantly increased in untreated diabetic mice (1.04 0.19 ul/g/h) compared to montelukast-treated mice (0.53 0.05 ul/g/h) and non-diabetic mice (0.32 0.05 ul/g/h). (p< 0.0001) Increased serum VEGF levels were detected in untreated diabetic mice, but not in non-diabetic or monteluast-treated diabetic mice. The isolated retinal microvasculature from untreated diabetic mice demonstrated a nearly 3-fold increase incapillary degeneration compared to nondiabetic mice. Remarkably, the number of degenerate retinal capillaries fell 75% with montelukast treatment. (p < 0.0001)
Pharmacologic inhibition of the leukotriene pathway holds potential as a novel therapy for prevention of diabetic retinopathy.
This PDF is available to Subscribers Only