Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways
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 effec...
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doaj-9635637beebb4c298a5fd6dffb6630fe2020-11-24T21:57:36ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-03-011010.3389/fphar.2019.00297448699Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival PathwaysFawad Ali Shah0Fawad Ali Shah1Gongping Liu2Gongping Liu3Lina T. Al Kury4Alam Zeb5Phil-Ok Koh6Muzaffar Abbas7Tao Li8Xifei Yang9Fang Liu10Fang Liu11Yuhua Jiang12Shupeng Li13Shupeng Li14Shupeng Li15State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, ChinaRiphah Institute of Pharmaceutical Sciences, Riphah International University Islamabad, Islamabad, PakistanKey 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, ChinaCo-innovation Center of Neuroregeneration, Nantong University, Nantong, ChinaCollege of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab EmiratesRiphah Institute of Pharmaceutical Sciences, Riphah International University Islamabad, Islamabad, PakistanDepartment of Anatomy, College of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, South KoreaDepartment of Pharmacy, Capital University of Science and Technology, Islamabad, PakistanDepartment of Forensic Medicine, School of Medicine, Xi’an Jiaotong University, Xi’an, ChinaCentre for Addiction and Mental Health, Campbell Research Institute, Toronto, ON, Canada0Department of Psychiatry, University of Toronto, Toronto, ON, Canada1Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, China2Cancer Centre, The Second Hospital of Shandong University, Jinan, ChinaState Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China0Department of Psychiatry, University of Toronto, Toronto, ON, Canada1Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen, ChinaStroke 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.https://www.frontiersin.org/article/10.3389/fphar.2019.00297/fullmelatoninischemic strokeNMDA receptorAMPA receptorPI3K/AKT/GSK3 pathway |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fawad Ali Shah Fawad Ali Shah Gongping Liu Gongping Liu Lina T. Al Kury Alam Zeb Phil-Ok Koh Muzaffar Abbas Tao Li Xifei Yang Fang Liu Fang Liu Yuhua Jiang Shupeng Li Shupeng Li Shupeng Li |
spellingShingle |
Fawad Ali Shah Fawad Ali Shah Gongping Liu Gongping Liu Lina T. Al Kury Alam Zeb Phil-Ok Koh Muzaffar Abbas Tao Li Xifei Yang Fang Liu Fang Liu Yuhua Jiang Shupeng Li Shupeng Li Shupeng Li Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways Frontiers in Pharmacology melatonin ischemic stroke NMDA receptor AMPA receptor PI3K/AKT/GSK3 pathway |
author_facet |
Fawad Ali Shah Fawad Ali Shah Gongping Liu Gongping Liu Lina T. Al Kury Alam Zeb Phil-Ok Koh Muzaffar Abbas Tao Li Xifei Yang Fang Liu Fang Liu Yuhua Jiang Shupeng Li Shupeng Li Shupeng Li |
author_sort |
Fawad Ali Shah |
title |
Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways |
title_short |
Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways |
title_full |
Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways |
title_fullStr |
Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways |
title_full_unstemmed |
Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways |
title_sort |
melatonin protects mcao-induced neuronal loss via nr2a mediated prosurvival pathways |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2019-03-01 |
description |
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. |
topic |
melatonin ischemic stroke NMDA receptor AMPA receptor PI3K/AKT/GSK3 pathway |
url |
https://www.frontiersin.org/article/10.3389/fphar.2019.00297/full |
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