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      Melatonin Mediates Protective Effects against Kainic Acid-Induced Neuronal Death through Safeguarding ER Stress and Mitochondrial Disturbance

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          Kainic acid (KA)-induced neuronal death is linked to mitochondrial dysfunction and ER stress. Melatonin is known to protect hippocampal neurons from KA-induced apoptosis, but the exact mechanisms underlying melatonin protective effects against neuronal mitochondria disorder and ER stress remain uncertain. In this study, we investigated the sheltering roles of melatonin during KA-induced apoptosis by focusing on mitochondrial dysfunction and ER stress mediated signal pathways. KA causes mitochondrial dynamic disorder and dysfunction through calpain activation, leading to neuronal apoptosis. Ca 2+ chelator BAPTA-AM and calpain inhibitor calpeptin can significantly restore mitochondrial morphology and function. ER stress can also be induced by KA treatment. ER stress inhibitor 4-phenylbutyric acid (PBA) attenuates ER stress-mediated apoptosis and mitochondrial disorder. It is worth noting that calpain activation was also inhibited under PBA administration. Thus, we concluded that melatonin effectively inhibits KA-induced calpain upregulation/activation and mitochondrial deterioration by alleviating Ca 2+ overload and ER stress.

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              The endoplasmic-reticulum (ER) stress response constitutes a cellular process that is triggered by a variety of conditions that disturb folding of proteins in the ER. Eukaryotic cells have developed an evolutionarily conserved adaptive mechanism, the unfolded protein response (UPR), which aims to clear unfolded proteins and restore ER homeostasis. In cases where ER stress cannot be reversed, cellular functions deteriorate, often leading to cell death. Accumulating evidence implicates ER stress-induced cellular dysfunction and cell death as major contributors to many diseases, making modulators of ER stress pathways potentially attractive targets for therapeutics discovery. Here, we summarize recent advances in understanding the diversity of molecular mechanisms that govern ER stress signaling in health and disease. This article is part of a Special Section entitled: Cell Death Pathways. © 2013.

                Author and article information

                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                28 February 2017
                : 10
                1Department of Biochemistry and Molecular Biology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
                2Department of Clinical Laboratory, Xi’an Third Hospital Xi’an, China
                3Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara CA, USA
                4Institute for Brain Research, Huazhong University of Science and Technology Wuhan, China
                5Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
                Author notes

                Edited by: Jiajie Diao, University of Cincinnati, USA

                Reviewed by: Kai Zhang, University of Illinois at Urbana-Champaign, USA; Min Liu, Harvard Medical School, USA; Da Xu, United States Department of Health and Human Services, USA

                *Correspondence: Juan Chen, chenjuanlinda69@ Anbing Shi, ashi@

                These authors have contributed equally to this work.

                Copyright © 2017 Xue, Shi, Chen, Hang, Xia, Wu, Tao, Zhou, Shi and Chen.

                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) or licensor 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.

                Figures: 9, Tables: 1, Equations: 0, References: 85, Pages: 16, Words: 0
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