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However, brain injury-induced energy and metabolic stressors, such as cerebral ischemia, increase AMPK phosphorylation. Phosphorylated AMPK contributes to excitotoxicity, oxidative, and metabolic problems. Furthermore, brain disease-induced release of zinc from synaptic vesicles contributes to neuronal damage via mechanisms including ROS production, apoptotic cell death, and DNA damage. For this reason, we hypothesized that regulating zinc accumulation and AMPK phosphorylation is critical for protection against global cerebral ischemia (GCI). Through virtual screening based on the structure of AMPK subunit alpha 2, we identified a novel compound, 2G11. In this study, we verified that 2G11 administration has neuroprotective effects via the blocking of zinc translocation and AMPK phosphorylation after GCI. As a result, we demonstrated that 2G11 protected hippocampal neurons against GCI and OGD\/R-derived cellular damage. In conclusion, we propose that AMPK inhibition and zinc chelation by 2G11 may be a promising tool for preventing GCI-induced hippocampal neuronal death.<\/jats:p>","DOI":"10.3390\/antiox11112192","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T02:43:51Z","timestamp":1667789031000},"page":"2192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Inhibition of Zinc Excitotoxicity and AMPK Phosphorylation by a Novel Zinc Chelator, 2G11, Ameliorates Neuronal Death Induced by Global Cerebral Ischemia"],"prefix":"10.3390","volume":"11","author":[{"given":"Dae Ki","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae-Won","family":"Eom","sequence":"additional","affiliation":[{"name":"Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A Ra","family":"Kho","sequence":"additional","affiliation":[{"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beom Seok","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Si Hyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae-Young","family":"Koh","sequence":"additional","affiliation":[{"name":"Neural Injury Research Laboratory, Department of Neurology, University of Ulsan College of Medicine, Seoul 05505, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0595-8547","authenticated-orcid":false,"given":"Yang-Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9579-3503","authenticated-orcid":false,"given":"Bo Young","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Physical Education, Hallym University, Chuncheon 24252, Korea"},{"name":"Institute of Sport Science, Hallym University, Chuncheon 24252, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Won","family":"Suh","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1152\/physrev.1999.79.4.1431","article-title":"Ischemic cell death in brain neurons","volume":"79","author":"Lipton","year":"1999","journal-title":"Physiol. 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