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            <front>

                <journal-meta>
                                    <journal-id></journal-id>
            <journal-title-group>
                                                                                    <journal-title>Veterinary Sciences and Practices</journal-title>
            </journal-title-group>
                                        <issn pub-type="epub">2822-3608</issn>
                                                                                            <publisher>
                    <publisher-name>Atatürk Üniversitesi</publisher-name>
                </publisher>
                    </journal-meta>
                <article-meta>
                                        <article-id pub-id-type="doi">10.5152/VetSciPract.2022.1033680</article-id>
                                                                <article-categories>
                                            <subj-group  xml:lang="en">
                                                            <subject>Veterinary Surgery</subject>
                                                    </subj-group>
                                            <subj-group  xml:lang="tr">
                                                            <subject>Veteriner Cerrahi</subject>
                                                    </subj-group>
                                    </article-categories>
                                                                                                                                                        <title-group>
                                                                                                                        <trans-title-group xml:lang="tr">
                                    <trans-title>Etanersept glutamat ile indüklenen nörotoksisiteye karşı nöronları korur: Bir in vitro çalışma</trans-title>
                                </trans-title-group>
                                                                                                                                                                                                <article-title>Etanercept Protects Neurons Against Glutamate-Induced Neurotoxicity: An In Vitro Study</article-title>
                                                                                                    </title-group>
            
                                                    <contrib-group content-type="authors">
                                                                        <contrib contrib-type="author">
                                                                    <contrib-id contrib-id-type="orcid">
                                        https://orcid.org/0000-0001-8836-9547</contrib-id>
                                                                <name>
                                    <surname>Ferah Okkay</surname>
                                    <given-names>Irmak</given-names>
                                </name>
                                                                    <aff>Department of Pharmacology, Atatürk University, Faculty of Pharmacy, Erzurum, Turkey</aff>
                                                            </contrib>
                                                    <contrib contrib-type="author">
                                                                    <contrib-id contrib-id-type="orcid">
                                        https://orcid.org/0000-0002-2871-0712</contrib-id>
                                                                <name>
                                    <surname>Okkay</surname>
                                    <given-names>Ufuk</given-names>
                                </name>
                                                                    <aff>Department of Medical Pharmacology, Atatürk University, Faculty of Medicine, Erzurum, Turkey; Vaccine Development Application and Research Center, Atatürk University, Turkey</aff>
                                                            </contrib>
                                                    <contrib contrib-type="author">
                                                                    <contrib-id contrib-id-type="orcid">
                                        https://orcid.org/0000-0002-6719-7077</contrib-id>
                                                                <name>
                                    <surname>Yeni</surname>
                                    <given-names>Yeşim</given-names>
                                </name>
                                                                    <aff>Department of Medical Pharmacology, Atatürk University, Faculty of Medicine, Erzurum, Turkey</aff>
                                                            </contrib>
                                                    <contrib contrib-type="author">
                                                                    <contrib-id contrib-id-type="orcid">
                                        https://orcid.org/0000-0003-4235-9241</contrib-id>
                                                                <name>
                                    <surname>Balpınar</surname>
                                    <given-names>Özge</given-names>
                                </name>
                                                                    <aff>Institute of Hemp Research Ondokuz Mayıs University, Samsun, Turkey</aff>
                                                            </contrib>
                                                    <contrib contrib-type="author">
                                                                    <contrib-id contrib-id-type="orcid">
                                        https://orcid.org/0000-0002-9658-3313</contrib-id>
                                                                <name>
                                    <surname>Hacımüftüoğlu</surname>
                                    <given-names>Ahmet</given-names>
                                </name>
                                                                    <aff>Department of Medical Pharmacology, Atatürk University, Faculty of Medicine, Erzurum, Turkey; Vaccine Development Application and Research Center, Atatürk University, Turkey</aff>
                                                            </contrib>
                                                                                </contrib-group>
                        
                                        <pub-date pub-type="pub" iso-8601-date="20221001">
                    <day>10</day>
                    <month>01</month>
                    <year>2022</year>
                </pub-date>
                                        <volume>17</volume>
                                        <issue>2</issue>
                                        <fpage>66</fpage>
                                        <lpage>70</lpage>
                        
                        <history>
                                    <date date-type="received" iso-8601-date="20211217">
                        <day>12</day>
                        <month>17</month>
                        <year>2021</year>
                    </date>
                                                    <date date-type="accepted" iso-8601-date="20220310">
                        <day>03</day>
                        <month>10</month>
                        <year>2022</year>
                    </date>
                            </history>
                                        <permissions>
                    <copyright-statement>Copyright © 2022, Veterinary Sciences and Practices</copyright-statement>
                    <copyright-year>2022</copyright-year>
                    <copyright-holder>Veterinary Sciences and Practices</copyright-holder>
                </permissions>
            
                                                                                                <trans-abstract xml:lang="tr">
                            <p>Mevcut çalışma, etanerseptin glutamat eksitotoksisitesinde koruyucu etkilerini, anti-inflamatuar ve anti-oksidan mekanizmalar yoluyla sıçan nöron kültüründe araştırmak için tasarlanmıştır. Sıçan kortikal nöronları glutamata maruz bırakıldı ve ardından etanerseptin glutamat toksisitesindeki etkisini değerlendirmek için etanersept çeşitli dozlarda (0.1, 0.5, 1, 10 μg/ml) uygulandı. Daha sonra nöronal hücre canlılığı, oksidatif stres ve inflamatuvar değişiklikleri inceledik. Etanerseptin, hücreleri glutamat eksitotoksisitesinden korudu. Hücre canlılığı analizlerimiz (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ve laktat dehidrogenaz), etanersept’in glutamat tarafından hasarlanan nöronların canlılık oranını belirgin şekilde arttırdığını ortaya koydu. Ayrıca, etanerseptin potansiyel antioksidan özellikleri MDA ve TOS gibi oksidatif stres parametrelerinin incelenmesi ve TAS ve SOD olarak ölçülen antioksidan parametreleri ile değerlendirildi. Ayrıca etanerseptin antiinflamatuar etkilerini değerlendirmek için TNF-α seviyeleri ölçüldü. Elde edilen veriler, etanercept’in inflamasyonu ve oksidatif parametreleri azaltırken antioksidatif parametrelerini arttırdığını kanıtladı. Bu çalışma, etanerseptin glutamat kaynaklı nöronal hücre ölümünü güçlü bir şekilde önlediğini göstermiştir. Bu çalışma, glutamat eksitotoksisitesine maruz kalan nöronlarda etanerseptin potansiyel koruyucu etkisini gösteren ilk çalışmadır ve etanerseptin terapötik potansiyeli hakkında yeni kapılar açmaktadır.</p></trans-abstract>
                                                                                                                                    <abstract><p>Current study was designed to investigate the protective effects of etanercept in glutamate excitotoxicity in rat neuronal culture through anti-inflammatory and anti-oxidant mechanisms. Rat cortical neurons were exposed to glutamate and to assess the effect of etanercept in glutamate toxicity, etanercept was applied at various doses (0.1, 0.5, 1, 10 μg/ml). Then we examined the changes in neuronal cell viability, oxidative stress and inflammation. Etanercept preserved cultured cells from glutamate excitotoxicity. Our cell viability analysis (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase) revealed that etanercept markedly increased the viability ratio of neurons injured by glutamate. In addition, the potential antioxidant property of etanercept was evaluated via the examination of oxidative stress parameters, such as MDA and TOS, and antioxidant parameters measured as TAS and SOD. Moreover, TNF-𝛼 levels were measured to evaluate anti-inflammatory effects of etanercept. Obtained data proved that etanercept increases the activity of the antioxidative parameters while decreased oxidative parameters and inflammation. The current study demonstrated that etanercept strongly prevents glutamate- induced neuronal cell death. This study is the first to demonstrate a potential protective effect of etanercept in neurons exposed to glutamate excitotoxicity and opens new doors on the therapeutic potential of etanercept.</p></abstract>
                                                            
            
                                                                                        <kwd-group>
                                                    <kwd>Etanercept</kwd>
                                                    <kwd>  glutamate</kwd>
                                                    <kwd>  in vitro</kwd>
                                                    <kwd>  neuroprotection</kwd>
                                                    <kwd>  oxidative stress</kwd>
                                            </kwd-group>
                            
                                                <kwd-group xml:lang="tr">
                                                    <kwd>Etanercept</kwd>
                                                    <kwd>  glutamate</kwd>
                                                    <kwd>  in vitro</kwd>
                                                    <kwd>  neuroprotection</kwd>
                                                    <kwd>  oxidative stress</kwd>
                                            </kwd-group>
                                                                                                                                        </article-meta>
    </front>
    <back>
                            <ref-list>
                                    <ref id="ref1">
                        <label>1</label>
                        <mixed-citation publication-type="journal">1. Albright TD, Jessell TM, Kandel ER, Posner MI. Neural science. Cell. 2000;100:1-55.</mixed-citation>
                    </ref>
                                    <ref id="ref2">
                        <label>2</label>
                        <mixed-citation publication-type="journal">2. Pinzón-Parra CA, Coatl-Cuaya H, Díaz A, Guevara J, Rodríguez-Moreno A, Flores G. Long-term effect of neonatal antagonism of ionotropic glutamate receptors on dendritic spines and cognitive
function in rats. J Chem Neuroanat. 2022;119:102054.</mixed-citation>
                    </ref>
                                    <ref id="ref3">
                        <label>3</label>
                        <mixed-citation publication-type="journal">3. Tripathi AS, Bansod P, Swathi KP. Activation of 5-HT 1b/d receptor restores the cognitive function by reducing glutamate release, deposition of beta-amyloid and TLR-4 pathway in the brain of scopolamine-induced dementia in rat. J Pharm Pharmacol. 2021;73(12):1592-1598.</mixed-citation>
                    </ref>
                                    <ref id="ref4">
                        <label>4</label>
                        <mixed-citation publication-type="journal">4. Song JH, Kang KS, Choi YK. Protective effect of casuarinin against glutamate-induced apoptosis in HT22 cells through inhibition of oxidative stress-mediated MAPK phosphorylation. Bioorg Med
Chem Lett. 2017;27(23):5109-5113.</mixed-citation>
                    </ref>
                                    <ref id="ref5">
                        <label>5</label>
                        <mixed-citation publication-type="journal">5. Hu Y, Feng X, Chen J, Wu Y, Shen L. Hydrogen-rich saline alleviates early brain injury through inhibition of necroptosis and neuroinflammation via the ROS/HO-1 signaling pathway after traumatic brain injury. Exp Ther Med. 2022;23(2):126.</mixed-citation>
                    </ref>
                                    <ref id="ref6">
                        <label>6</label>
                        <mixed-citation publication-type="journal">6. Ferah Okkay I, Okkay U, Cicek B, et al. Neuroprotective effect of bromelain in 6-hydroxydopamine induced in vitro model of Parkinson&#039;s disease. Mol Biol Rep. 2021;48(12):7711-7717.</mixed-citation>
                    </ref>
                                    <ref id="ref7">
                        <label>7</label>
                        <mixed-citation publication-type="journal">7. Floyd RA, Hensley K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiol Aging. 2002; 23(5):795-807.</mixed-citation>
                    </ref>
                                    <ref id="ref8">
                        <label>8</label>
                        <mixed-citation publication-type="journal">8. Kim HT, Prochiantz A, Kim JW. Donating Otx2 to support neighboring neuron survival. BMB Rep. 2016;49(2):69-70.</mixed-citation>
                    </ref>
                                    <ref id="ref9">
                        <label>9</label>
                        <mixed-citation publication-type="journal">9. Dalle-Donne I, Rossi R, Colombo R, Giustarini D, Milzani A. Biomarkers of oxidative damage in human disease. Clin Chem. 2006;52(4):601-623.</mixed-citation>
                    </ref>
                                    <ref id="ref10">
                        <label>10</label>
                        <mixed-citation publication-type="journal">10. Chamorro Á, Dirnagl U, Urra X, Planas AM. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol. 2016;15(8):869-881.</mixed-citation>
                    </ref>
                                    <ref id="ref11">
                        <label>11</label>
                        <mixed-citation publication-type="journal">11. Chen ZC, Zhong CJ. Oxidative stress in Alzheimer&#039;s disease. Neurosci Bull. 2014;30(2):271-281.</mixed-citation>
                    </ref>
                                    <ref id="ref12">
                        <label>12</label>
                        <mixed-citation publication-type="journal">12. Hansson E, Muyderman H, Leonova J, et al. Astroglia and glutamate in physiology and pathology: aspects on glutamate transport, glutamate-induced cell swelling and gap-junction communication. Neurochem Int. 2000;37(2-3):317-329.</mixed-citation>
                    </ref>
                                    <ref id="ref13">
                        <label>13</label>
                        <mixed-citation publication-type="journal">13. Karbownik M, Reiter RJ, Garcia JJ, Tan D. Melatonin reduces pheny lhydr azine -indu ced oxidative damage to cellular membranes: evidence for the involvement of iron. Int J Biochem Cell Biol. 2000;
32(10):1045-1054.</mixed-citation>
                    </ref>
                                    <ref id="ref14">
                        <label>14</label>
                        <mixed-citation publication-type="journal">14. Hertz L, Yu ACH, Kala G, Schousboe A. Neuronal-astrocytic and cytos olic- mitoc hondr ial metabolite trafficking during brain activation, hyperammonemia and energy deprivation. Neurochem Int. 2000;37(2-3):83-102.</mixed-citation>
                    </ref>
                                    <ref id="ref15">
                        <label>15</label>
                        <mixed-citation publication-type="journal">15. Ou W, Yang J, Simanauskaite J, et al. Biologic TNF-alpha inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy. J Neuroinflammation. 2021;18(1):312.</mixed-citation>
                    </ref>
                                    <ref id="ref16">
                        <label>16</label>
                        <mixed-citation publication-type="journal">16. Taguchi S, Azushima K, Yamaji T, et al. Effects of tumor necrosis factor-alpha inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy. Sci Rep. 2021;11:23587.</mixed-citation>
                    </ref>
                                    <ref id="ref17">
                        <label>17</label>
                        <mixed-citation publication-type="journal">17. Ren Z, Cui N, Zhu M, Khalil RA. TNFalpha blockade reverses vascular and uteroplacental matrix metalloproteinases imbalance and collagen accumulation in hypertensive pregnant rats. Biochem Pharmacol. 2021;193:114790.</mixed-citation>
                    </ref>
                                    <ref id="ref18">
                        <label>18</label>
                        <mixed-citation publication-type="journal">18. Pozniak PD, White MK, Khalili K. TNF-alpha/NF-kappaB signaling in the CNS: possible connection to EPHB2. J Neuroimmune Pharmacol. 2014;9(2):133-141.</mixed-citation>
                    </ref>
                                    <ref id="ref19">
                        <label>19</label>
                        <mixed-citation publication-type="journal">19. Kübra Elçioğlu H, Kabasakal L, Tufan F, et al. Effects of systemic thalidomide and intra cereb roven tricu lar etanercept and infliximab administration in a streptozotocin induced dementia model in rats. Acta Histochem. 2015;117(2):176-181.</mixed-citation>
                    </ref>
                                    <ref id="ref20">
                        <label>20</label>
                        <mixed-citation publication-type="journal">20. Kumari S, Mehta SL, Li PA. Glutamate induces mitochondrial dynamic imbalance and autophagy activation: preventive effects of selenium. PLOS ONE. 2012;7(6):e39382.</mixed-citation>
                    </ref>
                                    <ref id="ref21">
                        <label>21</label>
                        <mixed-citation publication-type="journal">21. Sattler R, Tymianski M. Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death. Mol Neurobiol. 2001;24(1-3):107-129.</mixed-citation>
                    </ref>
                                    <ref id="ref22">
                        <label>22</label>
                        <mixed-citation publication-type="journal">22. Feng X, Zhou Q, Liu C, Tao ML, Cao JG, Zhong ZH. Protective effect of 7-dif​luoro metho xy-5, 4′-Di -hydr oxyl isoflavone against the damage induced by glutamate in PC12 cells. Int J Mol Med. 2012;30(5):1159-1165.</mixed-citation>
                    </ref>
                                    <ref id="ref23">
                        <label>23</label>
                        <mixed-citation publication-type="journal">23. Schreihofer DA, Redmond L. Soy phytoestrogens are neuroprotective against stroke-like injury in vitro. Neuroscience. 2009;158(2):602-609.</mixed-citation>
                    </ref>
                                    <ref id="ref24">
                        <label>24</label>
                        <mixed-citation publication-type="journal">24. Rebai O, Belkhir M, Sanchez-Gomez MV, Matute C, Fattouch S, Amri M. Differential molecular targets for neuroprotective effect of chlorogenic acid and its related compounds against glutamate
induced excitotoxicity and oxidative stress in rat cortical neurons. Neurochem Res. 2017;42(12):3559-3572.</mixed-citation>
                    </ref>
                                    <ref id="ref25">
                        <label>25</label>
                        <mixed-citation publication-type="journal">25. Hirata Y, Yamamoto H, Atta MSM, Mahmoud S, Oh-hashi K, Kiuchi K. Chloroquine inhibits glutamate-induced death of a neuronal cell line by reducing reactive oxygen species through sigma-1 receptor. J Neurochem. 2011;119(4):839-847.</mixed-citation>
                    </ref>
                                    <ref id="ref26">
                        <label>26</label>
                        <mixed-citation publication-type="journal">26. Chen J, Chua KW, Chua CC, et al. Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity. Neurosci Lett. 2011;499(3):181-185.</mixed-citation>
                    </ref>
                                    <ref id="ref27">
                        <label>27</label>
                        <mixed-citation publication-type="journal">27. Kanki R, Nakamizo T, Yamashita H, et al. Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons. Brain Res. 2004;1015(1-2):73-81.</mixed-citation>
                    </ref>
                                    <ref id="ref28">
                        <label>28</label>
                        <mixed-citation publication-type="journal">28. Conrad M, Sato H. The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (-): cystine supplier and beyond. Amino Acids. 2012;42(1):231-246.</mixed-citation>
                    </ref>
                                    <ref id="ref29">
                        <label>29</label>
                        <mixed-citation publication-type="journal">29. Hasturk AE, Baran C, Yilmaz ER, et al. Etanercept prevents histopathological damage after spinal cord injury in rats. Asian J Neurosurg. 2018;13(1):37-45.</mixed-citation>
                    </ref>
                                    <ref id="ref30">
                        <label>30</label>
                        <mixed-citation publication-type="journal">30. Szelényi J. Cytokines and the central nervous system. Brain Res Bull. 2001;54(4):329-338.</mixed-citation>
                    </ref>
                                    <ref id="ref31">
                        <label>31</label>
                        <mixed-citation publication-type="journal">31. Gocmez SS, Yazir Y, Gacar G, et al. Etanercept improves aginginduced cognitive deficits by reducing inflammation and vascular dysfunction in rats. Physiol Behav. 2020;224:113019.</mixed-citation>
                    </ref>
                                    <ref id="ref32">
                        <label>32</label>
                        <mixed-citation publication-type="journal">32. Clark IA, Vissel B. Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents. J Neuroinflammation. 2016;13(1):236.</mixed-citation>
                    </ref>
                                    <ref id="ref33">
                        <label>33</label>
                        <mixed-citation publication-type="journal">33. Takeuchi H, Jin SJ, Wang JY, et al. Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem. 2006;
281(30):21362-21368.</mixed-citation>
                    </ref>
                                    <ref id="ref34">
                        <label>34</label>
                        <mixed-citation publication-type="journal">34. Morales I, Rodriguez M. Self-induced accumulation of glutamate in striatal astrocytes and basal ganglia excitotoxicity. Glia. 2012;60(10):1481-1494.</mixed-citation>
                    </ref>
                                    <ref id="ref35">
                        <label>35</label>
                        <mixed-citation publication-type="journal">35. Jing H, Hao YX, Bi Q, Zhang JZ, Yang PT. Intra-amygdala microinjection of TNF-alpha impairs the auditory fear conditioning of rats via glutamate toxicity. Neurosci Res. 2015;91:34-40.</mixed-citation>
                    </ref>
                                    <ref id="ref36">
                        <label>36</label>
                        <mixed-citation publication-type="journal">36. Chio CC, Lin JW, Chang MW, et al. Therapeutic evaluation of etanercept in a model of traumatic brain injury. J Neurochem. 2010;115(4):921-929.</mixed-citation>
                    </ref>
                                    <ref id="ref37">
                        <label>37</label>
                        <mixed-citation publication-type="journal">37. Kang YM, Wang Y, Yang LM, et al. TNF-alpha in hypothalamic paraventricular nucleus contributes to sympathoexcitation in heart failure by modulating AT1 receptor and neurotransmitters. Tohoku J Exp Med. 2010;222(4):251-263.</mixed-citation>
                    </ref>
                                    <ref id="ref38">
                        <label>38</label>
                        <mixed-citation publication-type="journal">38. Kang YM, He RL, Yang LM, et al. Brain tumour necrosis factor-alpha modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure. Cardiovasc Res. 2009;83(4):737-746.</mixed-citation>
                    </ref>
                            </ref-list>
                    </back>
    </article>
