Neurodegenerative influence of oxidative stress in the retina of a murine model of diabetes

Abstract

Aims/hypothesisDiabetic retinopathy is a progressive neurodegenerative disease, but the underlying mechanism is still obscure. Here, we focused on oxidative stress in the retina, and analysed its influence on retinal neurodegeneration, using an antioxidant, lutein.MethodsC57BL/6 mice with streptozotocin-induced diabetes were constantly fed either a lutein-supplemented diet or a control diet from the onset of diabetes, and their metabolic data were recorded. In 1-month-diabetic mice, reactive oxygen species (ROS) in the retina were measured using dihydroethidium and visual function was evaluated by electroretinograms. Levels of activated extracellular signal-regulated kinase (ERK), synaptophysin and brain-derived neurotrophic factor (BDNF) were also measured by immunoblotting in the retina of 1-month-diabetic mice. In the retinal sections of 4-month-diabetic mice, histological changes, cleaved caspase-3 and TUNEL staining were analysed.ResultsLutein did not affect the metabolic status of the diabetic mice, but it prevented ROS generation in the retina and the visual impairment induced by diabetes. ERK activation, the subsequent synaptophysin reduction, and the BDNF depletion in the diabetic retina were all prevented by lutein. Later, in 4-month-diabetic mice, a decrease in the thickness of the inner plexiform and nuclear layers, and ganglion cell number, together with increase in cleaved caspase-3- and TUNEL-positive cells, were avoided in the retina of lutein-fed mice.Conclusions/interpretationThe results indicated that local oxidative stress that has a neurodegenerative influence in the diabetic retina is prevented by constant intake of a lutein-supplemented diet. The antioxidant, lutein may be a potential therapeutic approach to protect visual function in diabetes.

Calcium Dobesilate Prevents Neurodegeneration and Vascular Leakage in Experimental Diabetes

“…The sections were examined using a laser confocal microscope as previously described. 29 Vascular leakage and PKC-delta assessment Vascular leakage was assessed by measuring albumin immunofluorescence as previously reported. 26 In addition, in order to further clarify the extra-vascular location of albumin, a double immunostaining for collagen (vascular wall marker) and albumin was performed.…”

Neuroinflammation and Neurodegenerative Disorders of the Retina

“…Our understanding of the underlying pathogenesis of diabetic retinopathy is becoming increasingly clear, largely due to experiments using animal disease models. Results of these studies have indicated that oxidative stress [6][7][8] and inflammatory signaling [7][8][9][10][11] in the retinal neural tissue are deeply involved in the disease-related mechanisms. A systemic increase in the level of oxidative stress is one of the characteristics of diabetes [12][13][14][15][16][17][18].…”

“…A systemic increase in the level of oxidative stress is one of the characteristics of diabetes [12][13][14][15][16][17][18]. In fact, Reactive Oxygen Species (ROS) were found to accumulate in the retinal neurons of a mouse diabetes model, using dihydroethidium (DHE), which reacts with superoxide to generate a fluorescent signal [7]. ROS are usually generated physiologically; however, when their levels exceed the capacity of anti-oxidative enzymes, such as the Superoxide Dismutases (SODs) and catalase, their accumulation leads to dysregulated cellular function.…”

“…ROS play a role in mediating various intracellular signaling pathways, including the pro-inflammatory MAPK, STAT, and NF-κB pathways [7,[20][21][22]. Thus, via ROS, proinflammatory signaling can be activated endogenously, even without exogenous cytokine stimuli, and cause neuroinflammation in a cell-autonomous fashion.…”

“…The levels of brain-derived neurotrophic factor (BDNF) [7] and nerve growth factor (NGF) [30] are both decreased in the diabetic retina. NGF is produced from pro-NGF by the proteolytic activity of matrix metalloproteinase (MMP)-7.…”