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      Longistyline C acts antidepressant in vivo and neuroprotection in vitro against glutamate-induced cytotoxicity by regulating NMDAR/NR2B-ERK pathway in PC12 cells

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          Abstract

          Depressive disorder is a common psychiatric disease which ranks among the leading cause of disability worldwide. The antidepressants presently used had low cure rate and caused a variety of side-effects. The screening of antidepressant drugs is usually used classic behavioural tests and neuroprotective strategy. Longistyline C, a natural stilbene isolated from the leaves of Cajanuscajan (L.) Millsp, was firstly investigated the antidepressant effect using animal behavioural tests, and studied the neuroprotection and its possible signaling pathways on glutamate-induced injury in PC12 cells. The results of animal test demonstrated that longistyline C had the antidepressant activity, which the effect is similar to the positive control. In current study, we investigated the effect of longistyline C on glutamate-induced injury in PC12 cells and explored its possible signaling pathways. The results demonstrated that pretreatment with longistyline C at the concentrations of 2–8 μmol/L for 24 h had a significant reduction of the cytotoxicity induced by glutamate (15 mmol/L) in PC12 cells using MTT, lactate dehydrogenase (LDH) release assay and Annexin V—PI double staining. Subsequently, we found that pretreatment with longistyline C (8 μmol/L) could drastically down-regulate the over-expression of NMDAR/NR2B and Ca 2+/calmodulin-dependent protein kinase II (CaMKII), up-regulate the expressions of p-ERK and p-CREB and alleviate ER stress. In conclusison, longistyline C is most possibly through regulating NMDAR/NR2B-ERK1/2 related pathway and restoring endoplasmic reticulum function to exert neuroprotective effect against glutamate-induced injury in PC12 cells.

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          Most cited references33

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          CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum.

          Cellular stress, particularly in response to toxic and metabolic insults that perturb function of the endoplasmic reticulum (ER stress), is a powerful inducer of the transcription factor CHOP. The role of CHOP in the response of cells to injury associated with ER stress was examined in a murine deficiency model obtained by homologous recombination at the chop gene. Compared with the wild type, mouse embryonic fibroblasts (MEFs) derived from chop -/- animals exhibited significantly less programmed cell death when challenged with agents that perturb ER function. A similar deficit in programmed cells death in response to ER stress was also observed in MEFs that lack CHOP's major dimerization partner, C/EBPbeta, implicating the CHOP-C/EBP pathway in programmed cell death. An animal model for studying the effects of chop on the response to ER stress was developed. It entailed exposing mice with defined chop genotypes to a single sublethal intraperitoneal injection of tunicamycin and resulted in a severe illness characterized by transient renal insufficiency. In chop +/+ and chop +/- mice this was associated with the early expression of CHOP in the proximal tubules followed by the development of a histological picture similar to the human condition known as acute tubular necrosis, a process that resolved by cellular regeneration. In the chop -/- animals, in spite of the severe impairment in renal function, evidence of cellular death in the kidney was reduced compared with the wild type. The proximal tubule epithelium of chop -/- animals exhibited fourfold lower levels of TUNEL-positive cells (a marker for programmed cell death), and significantly less evidence for subsequent regeneration. CHOP therefore has a role in the induction of cell death under conditions associated with malfunction of the ER and may also have a role in cellular regeneration under such circumstances.
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            The MAPK signaling cascade.

            The transmission of extracellular signals into their intracellular targets is mediated by a network of interacting proteins that regulate a large number of cellular processes. Cumulative efforts from many laboratories over the past decade have allowed the elucidation of one such signaling mechanism, which involves activations of several membranal signaling molecules followed by a sequential stimulation of several cytoplasmic protein kinases collectively known as mitogen-activated protein kinase (MAPK) signaling cascade. Up to six tiers in this cascade contribute to the amplification and specificity of the transmitted signals that eventually activate several regulatory molecules in the cytoplasm and in the nucleus to initiate cellular processes such as proliferation, differentiation, and development. Moreover, because many oncogenes have been shown to encode proteins that transmit mitogenic signals upstream of this cascade, the MAPK pathway provides a simple unifying explanation for the mechanism of action of most, if not all, nonnuclear oncogenes. The pattern of MAPK cascade is not restricted to growth factor signaling and it is now known that signaling pathways initiated by phorbol esters, ionophors, heat shock, and ligands for seven transmembrane receptors use distinct MAPK cascades with little or no cross-reactivity between them. In this review we emphasize primarily the first MAPK cascade to be discovered that uses the MEK and ERK isoforms and describe their involvement in different cellular processes.
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              MAPK cascade signalling and synaptic plasticity.

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                Author and article information

                Contributors
                Role: InvestigationRole: Writing – original draft
                Role: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Investigation
                Role: Project administration
                Role: ConceptualizationRole: Writing – review & editing
                Role: Project administration
                Role: Project administrationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 September 2017
                2017
                : 12
                : 9
                : e0183702
                Affiliations
                [001]Institute of Medicinal Plant Development, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, China
                Hokkaido Daigaku, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9128-7729
                Article
                PONE-D-16-47881
                10.1371/journal.pone.0183702
                5584824
                28873095
                0de2e844-0f5f-4903-9773-0dba0397b2d3
                © 2017 Liu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 20 December 2016
                : 9 August 2017
                Page count
                Figures: 11, Tables: 0, Pages: 19
                Funding
                Funded by: CAMS innovation Fund for Medical Sciences
                Award ID: 2016-I2M-1-012
                Award Recipient :
                This work was financially supported by CAMS innovation Fund for Medical Sciences (CIFMS)(2016-I2M-1-012). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurotransmitters
                Glutamate
                Biology and Life Sciences
                Neuroscience
                Neurochemistry
                Neurotransmitters
                Glutamate
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antidepressants
                Research and analysis methods
                Bioassays and physiological analysis
                Biochemical analysis
                Colorimetric assays
                MTT assay
                Research and analysis methods
                Bioassays and physiological analysis
                Biochemical analysis
                Enzyme assays
                MTT assay
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Biology and Life Sciences
                Biochemistry
                Oxidative Damage
                Reactive Oxygen Species
                Biology and Life Sciences
                Physiology
                Biological Locomotion
                Medicine and Health Sciences
                Physiology
                Biological Locomotion
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                Signaling cascades
                MAPK signaling cascades
                Biology and Life Sciences
                Zoology
                Animal Anatomy
                Tails
                Custom metadata
                The minimal underlying data set necessary for replication of this study is available within the paper and its Supporting Information files.

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