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      α-Melanocyte-stimulating hormone prevents glutamate excitotoxicity in developing chicken retina via MC4R-mediated down-regulation of microRNA-194

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          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.

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          Most cited references 51

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          Retinal ischemia: mechanisms of damage and potential therapeutic strategies.

          Retinal ischemia is a common cause of visual impairment and blindness. At the cellular level, ischemic retinal injury consists of a self-reinforcing destructive cascade involving neuronal depolarisation, calcium influx and oxidative stress initiated by energy failure and increased glutamatergic stimulation. There is a cell-specific sensitivity to ischemic injury which may reflect variability in the balance of excitatory and inhibitory neurotransmitter receptors on a given cell. A number of animal models and analytical techniques have been used to study retinal ischemia, and an increasing number of treatments have been shown to interrupt the "ischemic cascade" and attenuate the detrimental effects of retinal ischemia. Thus far, however, success in the laboratory has not been translated to the clinic. Difficulties with the route of administration, dosage, and adverse effects may render certain experimental treatments clinically unusable. Furthermore, neuroprotection-based treatment strategies for stroke have so far been disappointing. However, compared to the brain, the retina exhibits a remarkable natural resistance to ischemic injury, which may reflect its peculiar metabolism and unique environment. Given the increasing understanding of the events involved in ischemic neuronal injury it is hoped that clinically effective treatments for retinal ischemia will soon be available.
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            The changing landscape of ischaemic brain injury mechanisms.

            Thrombolysis has become established as an acute treatment for human stroke. But despite multiple clinical trials, neuroprotective strategies have yet to be proved effective in humans. Here we discuss intrinsic tissue mechanisms of ischaemic brain injury, and present a perspective that broadening of therapeutic targeting beyond excitotoxicity and neuronal calcium overload will be desirable for developing the most effective neuroprotective therapies.
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              Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death.

              Glutamate acting on N-methyl-D-aspartate (NMDA) receptors induces neuronal injury following stroke, through activation of poly(ADP-ribose) polymerase-1 (PARP-1) and generation of the death molecule poly(ADP-ribose) (PAR) polymer. Here we identify Iduna, a previously undescribed NMDA receptor-induced survival protein that is neuroprotective against glutamate NMDA receptor-mediated excitotoxicity both in vitro and in vivo and against stroke through interfering with PAR polymer-induced cell death (parthanatos). Iduna's protective effects are independent and downstream of PARP-1 activity. Iduna is a PAR polymer-binding protein, and mutation at the PAR polymer binding site abolishes the PAR binding activity of Iduna and attenuates its protective actions. Iduna is protective in vivo against NMDA-induced excitotoxicity and middle cerebral artery occlusion-induced stroke in mice. To our knowledge, these results define Iduna as the first known endogenous inhibitor of parthanatos. Interfering with PAR polymer signaling could be a new therapeutic strategy for the treatment of neurologic disorders.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                28 October 2015
                2015
                : 5
                Affiliations
                [1 ]Tianjin Medical University Eye Hospital, Tianjin Medical University Eye Institute, College of Optometry and Ophthalmology, Tianjin Medical University , Tianjin, 300384, China
                [2 ]Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University , Tianjin, 300071, China
                [3 ]Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin Key Laboratory of Molecular Nuclear Medicine , Tianjin, 300192, China
                [4 ]Department of Cardiology, Gansu Provincial Hospital , Lanzhou, Gansu Province, 730000, China
                [5 ]Tangshan Eye Hospital , Tangshan, Hebei Province, 063000, China
                Author notes
                Article
                srep15812
                10.1038/srep15812
                4623527
                26507936
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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