{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:57:33Z","timestamp":1760241453412,"version":"build-2065373602"},"reference-count":29,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2018,3,17]],"date-time":"2018-03-17T00:00:00Z","timestamp":1521244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre Poland","award":["2016\/23\/N\/NZ7\/01942"],"award-info":[{"award-number":["2016\/23\/N\/NZ7\/01942"]}]},{"name":"MMRC-KNOW","award":["2013-2017"],"award-info":[{"award-number":["2013-2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Hypoxia-ischemia (H-I) at the time of birth may cause neonatal death or lead to persistent brain damage. The search for an effective treatment of asphyxiated infants has not resulted in an effective therapy, and hypothermia remains the only available therapeutic strategy. Among possible experimental therapies, the induction of ischemic tolerance is promising. Recent investigations have shown that activation of group II metabotropic glutamate receptors (mGluR2\/3) can provide neuroprotection against H-I, but the mechanism of this effect is not clear. The aim of this study was to investigate whether an mGluR2\/3 agonist applied before H-I reduces brain damage in an experimental model of birth asphyxia and whether a decrease in oxidative stress plays a role in neuroprotection. Neonatal H-I on seven-day-old rats was used as an experimental model of birth asphyxia. Rats were injected intraperitoneally with the mGluR2\/3 agonist LY379268 24 or 1 h before H-I (5 mg\/kg). LY379268 reduced the infarct area in the ischemic hemisphere. Application of the agonist at both times also reduced the elevated levels of reactive oxygen species (ROS) in the ipsilateral hemisphere observed after H-I and prevented the increase in antioxidant enzyme activity in the injured hemisphere. The decrease in glutathione (GSH) level was also restored after agonist application. The results suggest that the neuroprotective mechanisms triggered by the activation of mGluR2\/3 before H-I act through the decrease of glutamate release and its extracellular concentration resulting in the inhibition of ROS production and reduction of oxidative stress. This, rather than induction of ischemic tolerance, is probably the main mechanism involved in the observed neuroprotection.<\/jats:p>","DOI":"10.3390\/brainsci8030048","type":"journal-article","created":{"date-parts":[[2018,3,20]],"date-time":"2018-03-20T06:57:11Z","timestamp":1521529031000},"page":"48","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pretreatment with Group II Metabotropic Glutamate Receptor Agonist LY379268 Protects Neonatal Rat Brains from Oxidative Stress in an Experimental Model of Birth Asphyxia"],"prefix":"10.3390","volume":"8","author":[{"given":"Ewelina","family":"Bratek","sequence":"first","affiliation":[{"name":"Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Apolonia","family":"Ziembowicz","sequence":"additional","affiliation":[{"name":"Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4212-221X","authenticated-orcid":false,"given":"Elzbieta","family":"Salinska","sequence":"additional","affiliation":[{"name":"Department of Neurochemistry, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1053\/j.semperi.2004.10.005","article-title":"Mechanisms of hypoxic-ischemic injury in the term infant","volume":"28","author":"McLean","year":"2004","journal-title":"Semin. Perinatol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhao, M., Zhu, P., Fujino, M., Zhuang, J., Guo, H., Sheikh, I., Zhao, L., and Li, X.K. (2016). Oxidative Stress in Hypoxic-Ischemic Encephalopathy: Molecular Mechanisms and Therapeutic Strategies. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17122078"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1089\/ars.2010.3576","article-title":"Oxidative stress in ischemic brain damage: Mechanisms of cell death and potential molecular targets for neuroprotection","volume":"14","author":"Chen","year":"2011","journal-title":"Antioxid Redox Signal."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.earlhumdev.2010.05.011","article-title":"Experimental treatments for hypoxic ischaemic encephalopathy","volume":"86","author":"Kelen","year":"2010","journal-title":"Early Hum. Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"33","DOI":"10.2174\/1871527314666150116112032","article-title":"Fetal asphyctic preconditioning protects against perinatal asphyxia- induced apoptosis and astrogliosis in neonatal brain","volume":"14","author":"Strackx","year":"2015","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.pneurobio.2013.12.007","article-title":"Non-pharmaceutical therapies for stroke: Mechanisms and clinical implications","volume":"115","author":"Chen","year":"2014","journal-title":"Prog. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.pneurobio.2013.11.005","article-title":"Preconditioning provides neuroprotection in models of CNS disease: Paradigms and clinical significance","volume":"114","author":"Stetler","year":"2014","journal-title":"Prog. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1111\/j.1527-3458.2007.00024.x","article-title":"The preclinical properties of a novel group II metabotropic glutamate receptor agonist LY379268","volume":"13","author":"Imre","year":"2007","journal-title":"CNS Drug Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/nrn2379","article-title":"Presynaptic glutamate receptors: Physiological functions and mechanisms of action","volume":"9","author":"Pinheiro","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3927","DOI":"10.1097\/00001756-199912160-00037","article-title":"Protection of neonatal rat brain from hypoxic-ischemic injury by LY379268, a Group II metabotropic glutamate receptor agonist","volume":"10","author":"Cai","year":"1999","journal-title":"Neuroreport"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/S0022-3565(24)39139-6","article-title":"Neuroprotective effects of LY379268, a selective mGlu2\/3 receptor agonist: Investigations into possible mechanism of action in vivo","volume":"294","author":"Bond","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_12","first-page":"303","article-title":"Effects of alpha-methyl-(4-tetrazolyl-phenyl) glycine on the induction of hippocampal ischemictolerance in the rat","volume":"55","author":"Feng","year":"2003","journal-title":"Sheng Li Xue Bao"},{"key":"ref_13","first-page":"182","article-title":"The role of NO resulted from neuronal nitric oxide synthase in the metabotropic glutamate receptor2\/3 mediated-brain ischemic tolerance","volume":"25","author":"Feng","year":"2009","journal-title":"Zhongguo Ying Yong Sheng Li Xue Za Zhi"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1111\/j.1471-4159.2006.04373.x","article-title":"Metabotropic glutamate receptor 3 protects neurons from glucose-induced oxidative injury by increasing intracellular glutathione concentration","volume":"101","author":"Russell","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1089\/scd.2015.0389","article-title":"Glutamate Increases In Vitro Survival and Proliferation and Attenuates Oxidative Stress-Induced Cell Death in Adult Spinal Cord-Derived Neural Stem\/Progenitor Cells via Non-NMDA Ionotropic Glutamate Receptors","volume":"25","author":"Hachem","year":"2016","journal-title":"Stem Cells Dev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.expneurol.2011.11.009","article-title":"Brain superoxide anion formation in immature rats during seizures: Protection by selected compounds","volume":"233","author":"Druga","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1097\/00004647-200103000-00010","article-title":"The metabotropic glutamate receptor system protects against ischemic free radical programmed cell death in rat brain endothelial cells","volume":"21","author":"Lin","year":"2001","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/S0306-4522(97)00347-3","article-title":"Differential compartmentalization of brain ascorbate and glutathione between neurons and glia","volume":"82","author":"Rice","year":"1998","journal-title":"Neuroscience"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1046\/j.1471-4159.1998.71031215.x","article-title":"Hypoxic preconditioning and hypoxic-ischemic brain damage in the immature rat: Pathologic and metabolic correlates","volume":"71","author":"Vannucci","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.coph.2014.12.002","article-title":"Metabotropic glutamate receptors as drug targets: What\u2019s new?","volume":"20","author":"Nicoletti","year":"2015","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9594","DOI":"10.1523\/JNEUROSCI.18-23-09594.1998","article-title":"Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta","volume":"18","author":"Bruno","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3905","DOI":"10.2174\/138161211798357719","article-title":"Nitric oxide-derived oxidants with a focus on peroxynitrite: Molecular targets, cellular responses and therapeutic implications","volume":"17","author":"Calcerrada","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_23","first-page":"92","article-title":"Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity","volume":"29","author":"Manucha","year":"2017","journal-title":"Clin. Investig. Arterioscler"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.ijdevneu.2007.08.010","article-title":"Genetic and pharmacologic manipulation of oxidative stress after neonatal hypoxia-ischemia","volume":"26","author":"Sheldon","year":"2008","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s11064-013-1191-0","article-title":"Hypobaric hypoxia postconditioning reduces brain damage and improves antioxidative defense in the model of birth asphyxia in 7-day-old rats","volume":"39","author":"Gamdzyk","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/nn2071","article-title":"Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses","volume":"11","author":"Papadia","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.redox.2018.01.008","article-title":"13 reasons why the brain is susceptible to oxidative stress","volume":"15","author":"Cobley","year":"2018","journal-title":"Redox Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1179\/135100002125000749","article-title":"Hypoxia-ischemia induces thioredoxin expression and nitrotyrosine formation in new-born rat brain","volume":"7","author":"Hattori","year":"2002","journal-title":"Redox Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.pneurobio.2017.01.001","article-title":"Preconditioning in neuroprotection: From hypoxia to ischemia","volume":"157","author":"Li","year":"2017","journal-title":"Prog. Neurobiol."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/8\/3\/48\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:57:27Z","timestamp":1760194647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/8\/3\/48"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,17]]},"references-count":29,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,3]]}},"alternative-id":["brainsci8030048"],"URL":"https:\/\/doi.org\/10.3390\/brainsci8030048","relation":{},"ISSN":["2076-3425"],"issn-type":[{"type":"electronic","value":"2076-3425"}],"subject":[],"published":{"date-parts":[[2018,3,17]]}}}