{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:41:04Z","timestamp":1791812464872,"version":"4.3.4"},"reference-count":39,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T00:00:00Z","timestamp":1666742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Russian State grant","award":["NSh-843.2022.3"],"award-info":[{"award-number":["NSh-843.2022.3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A non-surgical pharmacological approach to control cellular vitality and functionality during ischemic and\/or reperfusion-induced phases of strokes remains extremely important. The synthesis of 2-ethyl-6-methyl-3-hydroxypyridinium gammalactone-2,3-dehydro-L-gulonate (3-EA) was performed using a topochemical reaction. The cell-protective effects of 3-EA were studied on a model of glutamate excitotoxicity (GluTox) and glucose-oxygen deprivation (OGD) in a culture of NMRI mice cortical cells. Ca2+ dynamics was studied using fluorescent bioimaging and a Fura-2 probe, cell viability was assessed using cytochemical staining with propidium iodide, and gene expression was assessed by a real-time polymerase chain reaction. The compound anti-ischemic efficacy in vivo was evaluated on a model of irreversible middle cerebral artery (MCA) occlusion in Sprague-Dawley male rats. Brain morphological changes and antioxidant capacity were assessed one week after the pathology onset. The severity of neurological disorder was evaluated dynamically. 3-EA suppressed cortical cell death in a dose-dependent manner under the excitotoxic effect of glutamate and ischemia\/reoxygenation. Pre-incubation of cerebral cortex cells with 10\u2013100 \u00b5M 3-EA led to significant stagnation in Ca2+ concentration in a cytosol ([Ca2+]i) of neurons and astrocytes suffering GluTox and OGD. Decreasing intracellular Ca2+ and establishing a lower [Ca2+]i baseline inhibited necrotic cell death in an acute experiment. The mechanism of 3-EA cytoprotective action involved changes in the baseline and ischemia\/reoxygenation-induced expression of genes encoding anti-apoptotic proteins and proteins of the oxidative status; this led to inhibition of the late irreversible stages of apoptosis. Incubation of brain cortex cells with 3-EA induced an overexpression of the anti-apoptotic genes BCL-2, STAT3, and SOCS3, whereas the expression of genes regulating necrosis and inflammation (TRAIL, MLKL, Cas-1, Cas-3, IL-1\u03b2 and TNFa) were suppressed. 3-EA 18.0 mg\/kg intravenous daily administration for 7 days following MCA occlusion preserved rats\u2019 cortex neuron population, decreased the severity of neurological deficit, and spared antioxidant capacity of damaged tissues. 3-EA demonstrated proven short-term anti-ischemic activity in vivo and in vitro, which can be associated with antioxidant activity and the ability to target necrotic and apoptotic death. The compound may be considered a potential neuroprotective molecule for further pre-clinical investigation.<\/jats:p>","DOI":"10.3390\/ijms232112953","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T09:59:37Z","timestamp":1666778377000},"page":"12953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Novel Hydroxypyridine Compound Protects Brain Cells against Ischemic Damage In Vitro and In Vivo"],"prefix":"10.3390","volume":"23","author":[{"given":"Ekaterina","family":"Blinova","sequence":"first","affiliation":[{"name":"Department of Clinical Anatomy and Operative Surgery, Department of Pharmaceutics Technology and Pharmacology, Sechenov University, 8\/1 Trubetzkaya Street, 119991 Moscow, Russia"},{"name":"Department of Fundamental Medicine, National Research Nuclear University MEPHI, 31, Kashirskoe Highway, 115409 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2528-8798","authenticated-orcid":false,"given":"Egor","family":"Turovsky","sequence":"additional","affiliation":[{"name":"Institute of Cell Biophysics of the Russian Academy of Sciences, Federal Research Center \u201cPushchino Scientific Center for Biological Research of the Russian Academy of Sciences\u201d, 3 Institutskaya Street, 142290 Pushchino, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Eliseikina","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Department of Pathology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, 430005 Saransk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7881-2912","authenticated-orcid":false,"given":"Alexandra","family":"Igrunkova","sequence":"additional","affiliation":[{"name":"Department of Clinical Anatomy and Operative Surgery, Department of Pharmaceutics Technology and Pharmacology, Sechenov University, 8\/1 Trubetzkaya Street, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Semeleva","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Department of Pathology, National Research Ogarev Mordovia State University, 68 Bolshevistskaya Street, 430005 Saransk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grigorii","family":"Golodnev","sequence":"additional","affiliation":[{"name":"Department of Clinical Anatomy and Operative Surgery, Department of Pharmaceutics Technology and Pharmacology, Sechenov University, 8\/1 Trubetzkaya Street, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Termulaeva","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology and Drug Design, Department of Pharmaceutical Chemistry, All-Union Research Center for Biological Active Compounds Safety, 23 Kirova Street, 142450 Staraja Kupavna, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Vasilkina","sequence":"additional","affiliation":[{"name":"Department of Fundamental Medicine, National Research Nuclear University MEPHI, 31, Kashirskoe Highway, 115409 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Skachilova","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology and Drug Design, Department of Pharmaceutical Chemistry, All-Union Research Center for Biological Active Compounds Safety, 23 Kirova Street, 142450 Staraja Kupavna, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Mazov","sequence":"additional","affiliation":[{"name":"Department of Clinical Anatomy and Operative Surgery, Department of Pharmaceutics Technology and Pharmacology, Sechenov University, 8\/1 Trubetzkaya Street, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirill","family":"Zhandarov","sequence":"additional","affiliation":[{"name":"Department of Clinical Anatomy and Operative Surgery, Department of Pharmaceutics Technology and Pharmacology, Sechenov University, 8\/1 Trubetzkaya Street, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Simakina","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology and Drug Design, Department of Pharmaceutical Chemistry, All-Union Research Center for Biological Active Compounds Safety, 23 Kirova Street, 142450 Staraja Kupavna, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Belanov","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Pharmacology, Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health of the Russian Federation, 8\/2 Petrovsky Blvd, 127051 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4804-4398","authenticated-orcid":false,"given":"Saveliy","family":"Zalogin","sequence":"additional","affiliation":[{"name":"Department of Clinical Anatomy and Operative Surgery, Department of Pharmaceutics Technology and Pharmacology, Sechenov University, 8\/1 Trubetzkaya Street, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8385-4356","authenticated-orcid":false,"given":"Dmitrii","family":"Blinov","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Pharmacology and Drug Design, Department of Pharmaceutical Chemistry, All-Union Research Center for Biological Active Compounds Safety, 23 Kirova Street, 142450 Staraja Kupavna, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,26]]},"reference":[{"key":"ref_1","unstructured":"GBD 2019 Stroke Collaborators (2021). 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