Abstract
Retinal ischemia/reperfusion (I/R) injury is a major cause of vision loss in many ocular diseases. Retinal I/R injury is common in diabetic retinopathy, which as a result of hyperglycemia damages the retina and can cause blindness if left untreated. Inflammation is a major contributing factor in the pathogenesis of I/R injury. α-Melanocyte-stimulating hormone (α-MSH) is an anti-inflammatory peptide hormone that has displayed protective effects against I/R-induced organ damages. Here, we aimed to investigate the protective role of α-MSH on I/R-induced diabetic retinal damage using hyperglycemic C57BL/6J Ins2Akita/+ mice. Experimental I/R injury was induced by blocking the right middle cerebral artery (MCA) for 2 h followed by 2 h or 22 h of reperfusion using the intraluminal method. Since ophthalmic artery originates proximal to the origin of the MCA, the filament also blocked blood supply to the retina. Upon treatment with α-MSH at 1 h after ischemia and 1 h after reperfusion, animals displayed significant improvement in amplitudes of b-wave and oscillatory potentials during electroretinography. α-MSH also prevented I/R-induced histological alterations and inhibited the development of retinal swelling. Loss of retinal ganglion cells as well as oxidative stress were significantly attenuated in the α-MSH-treated retinae. Level of interleukin 10 was significantly increased after α-MSH treatment. Moreover, gene expression of glutamate aspartate transporter 1, monocarboxylate transporter (MCT) 1 and MCT-2 were significantly higher after α-MSH administration. In conclusion, α-MSH mitigates the severity of I/R-induced retinal damage under hyperglycemic condition. These beneficial effects of α-MSH may have important therapeutic implications against retinal I/R injury under hyperglycemic condition.
Highlights
Retinal ischemia is a major cause of vision loss and blindness, and is a common feature in various retinal disorders such as glaucoma, diabetic retinopathy (DR), central retinal artery (CRA), or vein occlusion, carotid artery disease, blood hyperviscosity, and retinopathy of prematurity (Osborne et al, 2004)
Retinal ischemia induces a wide range of deleterious effects, including excitotoxicity, inflammation, and oxidative stress
DR is associated with reduced retinal blood flow, dysfunction of the retinal neurons, followed by breakdown of blood-retinal barrier (BRB) and changes in visual function
Summary
Retinal ischemia is a major cause of vision loss and blindness, and is a common feature in various retinal disorders such as glaucoma, diabetic retinopathy (DR), central retinal artery (CRA), or vein occlusion, carotid artery disease, blood hyperviscosity, and retinopathy of prematurity (Osborne et al, 2004). Hyperglycemia leads to biochemical and cellular changes that trigger production of ROS as well as inflammatory cytokines and chemokines These mediators are major pathogenic factors causing retinal neuronal dysfunction, BRB breakdown and vascular leakage in early DR (Wang and Lo, 2018). Pericytes that line retinal capillaries are damaged due to sustained increase in PKCδ level, which are not reversed with return of normoglycemia (Geraldes et al, 2009) As a result, these changes can lead to localized areas of ischemia, edema, and angiogenesis, all of which can impair vision (Caldwell et al, 2003) through hemorrhage and tractional retinal detachment (Cai and Boulton, 2002). Anti-VEGF mediators can cause systemic complications due to their ability to enter systemic circulation (Simo and Hernandez, 2008).
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