Abstract
Diabetic retinopathy (DR) is a sight-threatening complication of diabetes. This study investigated the therapeutic effect of probucol in a mouse model of diabetic retinopathy. C57BL/6 mice were rendered diabetic through Streptozotocin (STZ) intraperitoneal injection. Mice were treated with probucol (150 mg/kg, gavage administration) or vehicle (DMSO) for 12 weeks. Optical coherence tomography (OCT), fundus photography (FP), and fundus fluorescein angiography (FFA) were conducted to evaluate retinal structure and damage. Eyes were collected for histology, reactive oxygen species (ROS) assay, apoptotic cells count, and western blot. After STZ injection, all mice developed hyperglycemia. Compared with the retina of the control group, the retina of diabetic mice showed enhanced arterial reflex and beaded vein dilatation. Besides, reduced inner and middle retinal thickness and significantly fewer nuclei were found in diabetic retina. Moreover, the diabetic retina also presented increased ROS generation and more TUNEL-positive cells. Probucol treatment prevented diabetes-induced lesions. In addition, the treatment also upregulated Nrf2 expression in diabetic retina. It was suggested that probucol attenuated diabetes-induced retinal neuronal degeneration via upregulating the Nrf2 signaling pathway possibly. Probucol may be repurposed for DR management.
Highlights
Diabetic retinopathy (DR) is the most common microvascular complication in diabetic patients and one of the major causes of acquired blindness worldwide [1]. e pathogenesis of DR is multifaceted and involves oxidative stress [2], proinflammatory changes [3], and the production of advanced glycation end products [4]. ese processes lead to dysfunction of multiple types of retinal cells, including vascular endothelial cells, pericytes, neurons damages, and glial cells.Preventative treatments for DR are limited, and most of the currently available treatments targeting DR are invasive.ere is a growing awareness of the importance of identifying protective pathways related to this condition
Oxidative stress is considered to be one of the main pathogeneses of DR [5]. e Nrf2 signaling pathway is considered to be part of the most important cellular pathway protecting against oxidative stress [6]. e Nrf2 signaling pathway regulates the expression of a large battery of endogenous protective genes involved in the cellular antioxidant defense systems [7]. ese protective genes play an important role in enhancing organizational antioxidant ability, as well as exerting antitoxin, antitumor, anti-inflammatory, and antiapoptotic effects [8,9,10]
We investigated the efficacy of probucol in the development of diabetic retinopathy using a mouse model of STZ-induced diabetes
Summary
Diabetic retinopathy (DR) is the most common microvascular complication in diabetic patients and one of the major causes of acquired blindness worldwide [1]. e pathogenesis of DR is multifaceted and involves oxidative stress [2], proinflammatory changes [3], and the production of advanced glycation end products [4]. ese processes lead to dysfunction of multiple types of retinal cells, including vascular endothelial cells, pericytes, neurons damages, and glial cells.Preventative treatments for DR are limited, and most of the currently available treatments targeting DR are invasive.ere is a growing awareness of the importance of identifying protective pathways related to this condition. E Nrf signaling pathway is considered to be part of the most important cellular pathway protecting against oxidative stress [6]. E Nrf signaling pathway regulates the expression of a large battery of endogenous protective genes involved in the cellular antioxidant defense systems [7]. Ese protective genes play an important role in enhancing organizational antioxidant ability, as well as exerting antitoxin, antitumor, anti-inflammatory, and antiapoptotic effects [8,9,10]. Ere are certain reports in the literature which indicate that probucol acts as a potent oxygen radical scavenger and can effectively prevent oxidative stress-induced tissue damage [13, 14]. Mori et al [17] found that probucol may show beneficial effects on diabetic retinopathy by preventing or slowing the impairment of the retinal circulation in patients
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