Abstract
Glutamate excitotoxicity is a common pathology to blinding ischemic retinopathies, such as diabetic retinopathy, glaucoma, and central retinal vein or artery occlusion. The development of an effective interventional modality to glutamate excitotoxicity is hence important to preventing blindness. Herein we showed that α-melanocyte-stimulating hormone (α-MSH) time-dependently protected against glutamate-induced cell death and tissue damage in an improved embryonic chicken retinal explant culture system. α-MSH down-regulated microRNA-194 (miR-194) expression during the glutamate excitotoxicity in the retinal explants. Furthermore, pharmacological antagonists to melanocortin 4 receptor (MC4R) and lentivirus-mediated overexpression of pre-miR-194 abrogated the suppressing effects of α-MSH on glutamate-induced activities of caspase 3 or 7, the ultimate enzymes for glutamate-induced cell death. These results suggest that the protective effects of α-MSH may be due to the MC4R mediated-down-regulation of miR-194 during the glutamate-induced excitotoxicity. Finally, α-MSH attenuated cell death and recovered visual functions in glutamate-stimulated post-hatch chick retinas. These results demonstrate the previously undescribed protective effects of α-MSH against glutamate-induced excitotoxic cell death in the cone-dominated retina both in vitro and in vivo, and indicate a novel molecular mechanism linking MC4R-mediated signaling to miR-194.
Highlights
The ionotropic receptors include N-methyl-D-aspartate (NMDA) receptor and non-NMDA receptors, which, in turn, contain α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptor and kainic acid (KA) receptor
Because retina is a natural extension of central nervous system, and oxidative stress is a direct trigger of cell death during glutamate excitotoxicity, it would be interesting to study the protective effects of α -Melanocyte-stimulating hormone (α -MSH) on glutamate excitotoxicity in retina
H&E staining showed that the structure of retinal explants cultured under 10% or 15% FBS at 3, 5, 7 days in vitro (DIV) was well-organized, with nuclear and plexiform layers clearly recognized and photoreceptor outer segments well developed and outward extended (Fig. 1D–I)
Summary
The ionotropic receptors include N-methyl-D-aspartate (NMDA) receptor and non-NMDA receptors, which, in turn, contain α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptor and kainic acid (KA) receptor. In the KA-induced excitotoxicity model, intraperitoneal injections of α -MSH reduced cell death in the CA1 pyramidal layer of hippocampus and inhibited reactive astrogliosis without affecting the protein levels of proinflammatory factors and brain-derived neurotrophic factor[22] This indicates the involvement of other regulatory mechanisms. In view of the neuroprotective function of MC4R, we hypothesize that α -MSH may exert protective effects against glutamate-induced excitotoxic cell death in retina through MC4R-mediated down-regulation of miR-194. To test this hypothesis, we chose a model of embryonic chicken retina that has long been recognized appropriate for studying glutamate excitotoxicity[30]. This study establishes a new link between MC4R signaling and miR-194, revealing a novel regulatory mechanism at the molecular level
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