Neuroprotective role of α-melanocyte-stimulating hormone on ischemia/reperfusion-induced brain and retinal damage in type 1 diabetic mouse

Abstract

Persons with type 1 diabetes have an increased risk of stroke compared with the general population. Because vision loss is frequently connected with stroke, it is essential to find a strategy that effectively preserves vision by protecting retina in addition to the brain. α-Melanocyte-stimulating hormone (α-MSH) is a neuropeptide that has protective effects against ischemia/reperfusion (I/R) induced organ damages. In this study, we aimed to investigate the neuroprotective role of α-MSH on I/R-induced brain and retinal damages after experimental stroke associated with hyperglycemia using C57BL/6J Ins2Akita/+ mice. Experimental stroke was induced by blocking the right middle cerebral artery (MCA) for 2 h with reperfusion for 2 h and 22 h, respectively using the intraluminal method. Since the opening of ophthalmic artery is proximal to the origin of the MCA, blood supply to the retina was also blocked by the filament. Animals were treated intraperitoneally with or without α-MSH at 1 h after ischemia and 1 h after reperfusion. Significantly higher percent survival and lower neurological scores were recorded in animals injected with α-MSH. Similarly, neuron death, glial cells activation as well as oxidative and nitrosative stress were significantly decreased in the α-MSH-treated brains. Relative intensities of matrix metallopeptidases 9, cyclooxygenase 2 and nuclear factor-κB were significantly decreased while intensities of Akt, heme oxygenase (HO) 1, HO-2 and B-cell lymphoma 2 were significantly increased in α-MSH treated brain. In addition, gene expressions of monocarboxylate transporter (MCT) 1, MCT-2 and activity-regulated cytoskeleton-associated protein were significantly higher in brain samples treated with α-MSH, suggesting an involvement of lactate metabolism in α-MSH neuroprotective effects. In the retina, α-MSH significantly increased the amplitude of b-wave as well as oscillatory potentials in electroretinogram, a measure of retinal function. 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 α-MSH-treated diabetic retina after I/R injury. Expression of interleukin 10 was significantly increased in the retina after α-MSH treatment. In addition, gene expression of MCT-1, MCT-2 and glutamate aspartate transporter 1 were significantly higher after α-MSH administration. In conclusion, α-MSH is neuroprotective under hyperglycemic condition against I/R-induced brain and retinal damage by its anti-inflammatory, anti-oxidative and anti-apoptotic properties. These effects of α-MSH may have important therapeutic implication against cerebral and retinal I/R injury under hyperglycemic condition.