Purpose : Diabetic retinopathy (DR) is a common neurovascular complication of diabetes. Retinal accumulation of the acrolein-derived advanced lipoxidation end-product, FDP-lysine (N^ε-(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.

目的：糖尿病视网膜病变（DR）是糖尿病常见的神经血管并发症。丙烯醛衍生的高级脂氧化终产物 FDP-赖氨酸 (N ^ε -(3-formyl-3,4-dehydropiperidino-lysine) 的视网膜积累与这种情况的发病机制有关。我们已经确定了一种新药称为 2-HDP 可有效清除丙烯醛并防止糖尿病期间视网膜 FDP-赖氨酸积累。本研究的目的是确定 2-HDP 是否可以预防糖尿病期间的神经血管功能障碍。

方法：雄性Sprague-Dawley大鼠分为三组：（1）非糖尿病组；(2) 链脲佐菌素诱发的糖尿病；(3) 在饮用水中加入 2-HDP 治疗的糖尿病患者。在糖尿病诱导后 1、3 和 6 个月测量血压、体重、饮水量、HbA1c 和视网膜电图 (ERG) 的体内分析。进行免疫标记、蛋白质印迹、细胞因子阵列和埃文蓝染料测定以研究视网膜的血管、神经元和神经胶质成分。进行分子动力学 (MD) 模拟以研究 2-HDP 药物在细胞膜上的渗透。

结果：糖尿病对照组在糖尿病 3 个月和 6 个月后，ERG a 波和 b 波振幅显着降低，而这些变化通过 2-HDP 治疗完全被阻止（P<0.01）。该药物还可以防止视网膜 FDP-赖氨酸积累、Müller 细胞和小胶质细胞的活化，以及糖尿病视网膜的神经和血管退行性变化（P<0.05）。MD 模拟表明，大多数 2-HDP 分子是质子化的，不容易穿过细胞膜。

结论：我们的研究为丙烯醛和 FDP-赖氨酸在与 DR 相关的神经血管病变发展中的关键作用提供了强有力的证据。

该摘要于 2022 年 5 月 1 日至 4 日在科罗拉多州丹佛市举行的 2022 年 ARVO 年会上以虚拟形式呈现。