Montelukast Prevents Early Diabetic Retinopathy in Mice.

Abstract

Chronic inflammation and oxidative stress are critical components in the pathogenic cascade of early diabetic retinopathy, characterized by neuronal and vascular degeneration. We investigated pharmacologic inhibition of the proinflammatory leukotriene cascade for therapeutic benefit in early diabetic retinopathy. Using the streptozotocin-induced diabetes mouse model, we administered montelukast, a leukotriene receptor antagonist, and diabetes-related retinal pathology was assessed. Early biochemical and cellular function measures were evaluated at 3 months’ diabetes duration and included vascular permeability, superoxide production, leukotriene generation, leukocyte-induced microvascular endothelial cell death, and retinal function by electroretinography. Histopathology assessments at 9 months’ diabetes duration included capillary degeneration and retinal ganglion cell loss. Leukotriene receptor antagonism resulted in a significant reduction of early, diabetes-induced retinal capillary leakage, superoxide generation, leukocyte adherence, and leukotriene generation. After 9 months of diabetes, the retinal microvasculature from untreated diabetic mice demonstrated a nearly threefold increase in capillary degeneration compared with nondiabetic mice. Montelukast inhibited the diabetes-induced capillary and neuronal degeneration, whether administered as a prevention strategy, immediately after induction of diabetes, or as an intervention strategy starting at 4.5 months after confirmation of diabetes. Pharmacologic blockade of the leukotriene pathway holds potential as a novel therapy to prevent or slow the development of diabetic retinopathy.