Anti-inflammatory α-Melanocyte-Stimulating Hormone Protects Retina After Ischemia/Reperfusion Injury in Type I Diabetes

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.

Alpha-Melanocyte-Stimulating Hormone Maintains Retinal Homeostasis after Ischemia/Reperfusion

“…Treatment of diabetic rodent models with α-MSH suppresses the retinopathy and also suppresses the extent of retinal damage caused by central vein occlusion in diabetic stroke mice models [21,24,25,43]. The actions of α-MSH are not restricted to diabetic conditions and are mostly on the cellular response to injury and inflammation [14,15,17].…”

“…The neuropeptide suppresses the migration and infiltration of polymorphonuclear leukocytes into the anterior chamber of eyes with endotoxin-induced uveitis [45,46]. In diabetic mice, α-MSH treatment suppresses the pathology of diabetic retinopathy by promoting the survival of both ganglion cells and photoreceptors, with the retention of the bloodocular barrier and the inhibition of the induction of neovascularization [21,24,25,43]. The loss of photoreceptors in RCS rat retinas is retained with α-MSH treatment [38].…”

“…Diabetic mice and rats treated with α-MSH or melanocortin receptor agonists have suppressed pathology and cytokines of diabetic retinopathy, including the retention of viable photoreceptors and ganglion cells [20][21][22][23][24]. In addition, mice with central vein occlusions survive longer with reduced stroke and retinal pathology following α-MSH treatment [25]. The anti-inflammatory and cell-surviving signals of α-MSH may be a viable treatment for acute IRI.…”

Stimulating the Melanocortin System in Uveitis and Diabetes Preserves the Structure and Anti-Inflammatory Activity of the Retina

“…In addition, α-MSH treatment may signal retinal cell survival or inhibit apoptosis signals [ 6 , 18 , 33 , 35 , 36 ]. It has been demonstrated that using α-MSH as a treatment protects the retina from degeneration caused by EAU, diabetic retinopathy, and ischemia/reperfusion [ 18 , 19 , 21 , 26 , 37 , 38 , 39 , 40 ]. While experimentally using α-MSH has demonstrated benefits, α-MSH is a highly unstable molecule [ 41 ].…”

“…The suppression of EAU by PL-8331-treatment showed that by activating the melanocortin-signaling pathways, there was the suppression of inflammation and preservation of retinal structure similar to what others have seen using native α-MSH [ 16 , 19 , 43 , 44 , 45 ]. The literature describes the potential of stimulating the melanocortin signaling pathways to promote the survival of retinal cells [ 19 , 27 , 33 , 37 , 43 , 46 , 47 , 48 ]. The histology of the EAU retinas showed that PL-8331 treatment observably protects the photoreceptor layer.…”