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      Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways

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          Abstract

          Stroke is the significant cause of human mortality and sufferings depending upon race and demographic location. Melatonin is a potent antioxidant that exerts protective effects in differential experimental stroke models. Several mechanisms have been previously suggested for the neuroprotective effects of melatonin in ischemic brain injury. The aim of this study is to investigate whether melatonin treatment affects the glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor signaling in cerebral cortex and striatum 24 h after permanent middle cerebral artery occlusion (MCAO). Melatonin (5 mg/kg) attenuated ischemia-induced down regulation of NMDA receptor 2 (NR2a), postsynaptic density-95 (PSD95) and increases NR2a/PSD95 complex association, which further activates the pro-survival PI3K/Akt/GSK3β pathway with mitigated collapsin response mediator protein 2 (CRMP2) phosphorylation. Furthermore, melatonin increases the expression of γ-enolase, a neurotrophic factor in ischemic cortex and striatum, and preserve the expression of presynaptic (synaptophysin and SNAP25) and postsynaptic (p-GluR1845) protein. Our study demonstrated a novel neuroprotective mechanism for melatonin in ischemic brain injury which could be a promising neuroprotective agent for the treatment of ischemic stroke.

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          Most cited references 58

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          Update of the stroke therapy academic industry roundtable preclinical recommendations.

          The initial Stroke Therapy Academic Industry Roundtable (STAIR) recommendations published in 1999 were intended to improve the quality of preclinical studies of purported acute stroke therapies. Although recognized as reasonable, they have not been closely followed nor rigorously validated. Substantial advances have occurred regarding the appropriate quality and breadth of preclinical testing for candidate acute stroke therapies for better clinical translation. The updated STAIR preclinical recommendations reinforce the previous suggestions that reproducibly defining dose response and time windows with both histological and functional outcomes in multiple animal species with appropriate physiological monitoring is appropriate. The updated STAIR recommendations include: the fundamentals of good scientific inquiry should be followed by eliminating randomization and assessment bias, a priori defining inclusion/exclusion criteria, performing appropriate power and sample size calculations, and disclosing potential conflicts of interest. After initial evaluations in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions such as hypertension, diabetes, and hypercholesterolemia. Another consideration is the use of clinically relevant biomarkers in animal studies. Although the recommendations cannot be validated until effective therapies based on them emerge from clinical trials, it is hoped that adherence to them might enhance the chances for success.
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            Mechanisms, challenges and opportunities in stroke.

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              Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways.

              Here we report that synaptic and extrasynaptic NMDA (N-methyl-D-aspartate) receptors have opposite effects on CREB (cAMP response element binding protein) function, gene regulation and neuron survival. Calcium entry through synaptic NMDA receptors induced CREB activity and brain-derived neurotrophic factor (BDNF) gene expression as strongly as did stimulation of L-type calcium channels. In contrast, calcium entry through extrasynaptic NMDA receptors, triggered by bath glutamate exposure or hypoxic/ischemic conditions, activated a general and dominant CREB shut-off pathway that blocked induction of BDNF expression. Synaptic NMDA receptors have anti-apoptotic activity, whereas stimulation of extrasynaptic NMDA receptors caused loss of mitochondrial membrane potential (an early marker for glutamate-induced neuronal damage) and cell death. Specific blockade of extrasynaptic NMDA receptors may effectively prevent neuron loss following stroke and other neuropathological conditions associated with glutamate toxicity.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                29 March 2019
                2019
                : 10
                Affiliations
                1State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School , Shenzhen, China
                2Riphah Institute of Pharmaceutical Sciences, Riphah International University Islamabad , Islamabad, Pakistan
                3Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
                4Co-innovation Center of Neuroregeneration, Nantong University , Nantong, China
                5College of Natural and Health Sciences, Zayed University , Abu Dhabi, United Arab Emirates
                6Department of Pharmacy, Capital University of Science and Technology , Islamabad, Pakistan
                7Department of Forensic Medicine, School of Medicine, Xi’an Jiaotong University , Xi’an, China
                8Centre for Addiction and Mental Health, Campbell Research Institute , Toronto, ON, Canada
                9Department of Psychiatry, University of Toronto , Toronto, ON, Canada
                10Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention , Shenzhen, China
                11Cancer Centre, The Second Hospital of Shandong University , Jinan, China
                Author notes

                Edited by: Francisco Lopez-Munoz, Universidad Camilo José Cela, Spain

                Reviewed by: Mustafa Caglar Beker, Istanbul Medipol University, Turkey; Izaskun Buendia, Institute of Health Research of the University Hospital of La Princesa, Spain

                These authors have contributed equally to this work

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2019.00297
                6461025
                Copyright © 2019 Shah, Liu, Al Kury, Zeb, Abbas, Li, Yang, Liu, Jiang and Li.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 59, Pages: 11, Words: 0
                Categories
                Pharmacology
                Original Research

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