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      Neuroprotective effects of melatonin and celecoxib against ethanol-induced neurodegeneration: a computational and pharmacological approach

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          Abstract

          Purpose

          Melatonin and celecoxib are antioxidants and anti-inflammatory agents that exert protective effects in different experimental models. In this study, the neuroprotective effects of melatonin and celecoxib were demonstrated against ethanol-induced neuronal injury by in silico, morphological, and biochemical approaches.

          Methods

          For the in silico study, 3-D structures were constructed and docking analysis performed. For in vivo studies, rats were treated with ethanol, melatonin, and celecoxib. Brain samples were collected for biochemical and morphological analysis.

          Results

          Homology modeling was performed to build 3-D structures for IL1β), TNFα, TLR4, and inducible nitric oxide synthase. Structural refinement was achieved via molecular dynamic simulation and processed for docking and postdocking analysis. Further in vivo experiments showed that ethanol induced marked neuronal injury characterized by downregulated glutathione, glutathione S-transferase, and upregulated inducible nitric oxide synthase. Additionally, ethanol increased the expression of TNFα and IL1β. Finally, neuronal apoptosis was demonstrated in ethanol-intoxicated animals using caspase 3 and activated JNK staining. On the other hand, melatonin and celecoxib treatment ameliorated the biochemical and immunohistochemical alterations induced by ethanol.

          Conclusion

          These results demonstrated that ethanol induced neurodegeneration by activating inflammatory and apoptotic proteins in rat brain, while melatonin and celecoxib may protect rat brain by downregulating inflammatory and apoptotic markers.

          Most cited references40

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          Multiple sequence alignment with the Clustal series of programs.

          R Chenna (2003)
          The Clustal series of programs are widely used in molecular biology for the multiple alignment of both nucleic acid and protein sequences and for preparing phylogenetic trees. The popularity of the programs depends on a number of factors, including not only the accuracy of the results, but also the robustness, portability and user-friendliness of the programs. New features include NEXUS and FASTA format output, printing range numbers and faster tree calculation. Although, Clustal was originally developed to run on a local computer, numerous Web servers have been set up, notably at the EBI (European Bioinformatics Institute) (http://www.ebi.ac.uk/clustalw/).
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            Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis.

            Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.
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              Hydrogen bonding in globular proteins

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                02 August 2019
                2019
                : 13
                : 2715-2727
                Affiliations
                [1 ] College of Natural and Health Sciences, Zayed University , Abu Dhabi, United Arab Emirates
                [2 ] Riphah Institute of Pharmaceutical Sciences, Riphah International University , Islamabad, Pakistan
                [3 ] Department of Pharmacy, Quaid-I-Azam University , Islamabad, Pakistan
                [4 ] Rehman Medical Institute , Peshawar, Pakistan
                [5 ] State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School , Shenzhen 518055, People’s Republic of China
                Author notes
                Correspondence: Fawad Ali ShahRiphah Institute of Pharmaceutical Sciences, Riphah International University , Islamabad, PakistanTel +92 512 891 8358Fax +92 51 289 0690Email fawad.shah@ 123456riphah.edu.pk
                Shupeng LiState Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School , Shenzhen518055, People’s Republic of ChinaTel +86 7 552 603 2325Email lisp@ 123456pkusz.edu.cn
                Article
                207310
                10.2147/DDDT.S207310
                6683968
                9d2e5d76-0791-42f3-9f2c-5ecab0cb75be
                © 2019 Al Kury et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 01 March 2019
                : 27 June 2019
                Page count
                Figures: 6, Tables: 2, References: 54, Pages: 13
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                simulation,docking,cortex,hippocampus,ethanol,neurodegeneration
                Pharmacology & Pharmaceutical medicine
                simulation, docking, cortex, hippocampus, ethanol, neurodegeneration

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