Abstract
Purpose :
Diabetic retinopathy (DR) is a common neurovascular complication of diabetes. Retinal accumulation of the acrolein-derived advanced lipoxidation end-product, FDP-lysine (Nε-(3-formyl-3,4-dehydropiperidino-lysine), has been implicated in the pathogenesis of this condition. We have identified a new drug called 2-HDP that is effective in scavenging acrolein and preventing retinal FDP-lysine accumulation during diabetes. The aim of this study was to determine whether 2-HDP can protect against neurovascular dysfunction during diabetes.
Methods :
Male Sprague-Dawley rats were divided into three groups: (1) non-diabetic; (2) streptozotocin-induced diabetic; and (3) diabetic treated with 2-HDP administrated in their drinking water. In vivo analysis of blood pressure, body weights, water intake, HbA1c and electroretinography (ERG) were measured at 1-,3- and 6-months after diabetes induction. Immunolabelling, western blotting, cytokine arrays and the Evan’s blue dye assay were carried out to study the vascular, neuronal, and glial components of the retina. Molecular Dynamics (MD) simulations were performed to investigate 2-HDP drug permeation across cellular membranes.
Results :
ERG a- and b-wave amplitudes were significantly reduced in diabetic controls after 3- and 6-months of diabetes and these changes were completely prevented by treatment with 2-HDP (P<0.01). This drug also prevented retinal FDP-lysine accumulation, the activation of Müller cells and microglia, and neuro and vasodegenerative changes in the diabetic retina (P<0.05). MD simulations have revealed that most 2-HDP molecules are protonated and do not readily cross cell membranes.
Conclusions :
Our studies provide strong evidence for a key role of acrolein and FDP-lysine in the development of the neurovascular lesions associated with DR.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.