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An increase in reactive oxygen species (ROS) production induces apoptotic processes resulting in neuronal death. Activation of group II mGluR was shown to prevent neuronal damage after HI. The application of agonists of mGluR3 (N\u2010acetylaspartylglutamate; NAAG) or mGluR2 (LY379268) inhibits the release of glutamate and reduces neurodegeneration in a neonatal rat model of HI, although the exact mechanism is not fully recognized. In the present study, the effects of NAAG (5\u2009mg\/kg) and LY379268 (5\u2009mg\/kg) application (24\u2009h or 1\u2009h before experimental birth asphyxia) on apoptotic processes as the potential mechanism of neuroprotection in 7\u2010day\u2010old rats were investigated. Intraperitoneal application of NAAG or LY379268 at either time point before HI significantly reduced the number of TUNEL\u2010positive cells in the CA1 region of the ischemic brain hemisphere. Both agonists reduced expression of the proapoptotic Bax protein and increased expression of Bcl\u20102. Decreases in HI\u2010induced caspase\u20109 and caspase\u20103 activity were also observed. Application of NAAG or LY379268 24\u2009h or 1\u2009h before HI reduced HIF\u20101<jats:italic>\u03b1<\/jats:italic> formation likely by reducing ROS levels. It was shown that LY379268 concentration remains at a level that is required for activation of mGluR2 for up to 24\u2009h; however, NAAG is quickly metabolized by glutamate carboxypeptidase II (GCPII) into glutamate and N\u2010acetyl\u2010aspartate. The observed effect of LY379268 application 24\u2009h or 1\u2009h before HI is connected with direct activation of mGluR2 and inhibition of glutamate release. Based on the data presented in this study and on our previous findings, we conclude that the neuroprotective effect of NAAG applied 1\u2009h before HI is most likely the result of a combination of mGluR3 and NMDA receptor activation, whereas the beneficial effects of NAAG pretreatment 24\u2009h before HI can be explained by the activation of NMDA receptors and induction of the antioxidative\/antiapoptotic defense system triggered by mild excitotoxicity in neurons. This response to NAAG pretreatment is consistent with the commonly accepted mechanism of preconditioning.<\/jats:p>","DOI":"10.1155\/2021\/8848015","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T16:05:13Z","timestamp":1615305913000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Pretreatment with mGluR2 or mGluR3 Agonists Reduces Apoptosis Induced by Hypoxia\u2010Ischemia in Neonatal Rat Brains"],"prefix":"10.1155","volume":"2021","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1840-0267","authenticated-orcid":false,"given":"Ewelina","family":"Bratek - Gerej","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Bronisz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apolonia","family":"Ziembowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elzbieta","family":"Salinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.3390\/metabo10040141"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2017.00078"},{"key":"e_1_2_8_3_2","article-title":"Perinatal asphyxia","volume":"2007","author":"McGuire W.","year":"2007","journal-title":"BMJ Clinical Evidence"},{"key":"e_1_2_8_4_2","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.01064"},{"key":"e_1_2_8_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2009.09.002"},{"key":"e_1_2_8_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2003.015032"},{"key":"e_1_2_8_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000258979.92828.bc"},{"key":"e_1_2_8_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2009.09.006"},{"key":"e_1_2_8_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2020.106354"},{"key":"e_1_2_8_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.25074"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00060-08"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ultrasmedbio.2018.04.005"},{"key":"e_1_2_8_13_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0200933"},{"key":"e_1_2_8_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2005.12.022"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2012.06.005"},{"key":"e_1_2_8_16_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568007023339328"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.2174\/1874473710902010083"},{"key":"e_1_2_8_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2016.02.042"},{"key":"e_1_2_8_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14061"},{"key":"e_1_2_8_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2008.07.045"},{"key":"e_1_2_8_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1300672"},{"key":"e_1_2_8_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0601267103"},{"key":"e_1_2_8_23_2","first-page":"800","article-title":"Neuroprotective effects of LY379268, a selective mGlu2\/3 receptor agonist: investigations into possible mechanism of action in vivo","volume":"294","author":"Bond A.","year":"2000","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"e_1_2_8_24_2","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-199912160-00037"},{"key":"e_1_2_8_25_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2000.0750443.x"},{"key":"e_1_2_8_26_2","first-page":"796","article-title":"N-acetyl-aspartylglutamate modulation of N-methyl-D-aspartate-stimulated [3H]norepinephrine release from rat hippocampal slices","volume":"266","author":"Puttfarcken P. 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