{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:19:32Z","timestamp":1772252372825,"version":"3.50.1"},"reference-count":68,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T00:00:00Z","timestamp":1595548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["16-15-10192"],"award-info":[{"award-number":["16-15-10192"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Pathological homocysteine (HCY) accumulation in the human plasma, known as hyperhomocysteinemia, exacerbates neurodegenerative diseases because, in the brain, this amino acid acts as a persistent N-methyl-d-aspartate receptor agonist. We studied the effects of 0.1\u20131 nM ouabain on intracellular Ca2+ signaling, mitochondrial inner membrane voltage (\u03c6mit), and cell viability in primary cultures of rat cortical neurons in glutamate and HCY neurotoxic insults. In addition, apoptosis-related protein expression and the involvement of some kinases in ouabain-mediated effects were evaluated. In short insults, HCY was less potent than glutamate as a neurotoxic agent and induced a 20% loss of \u03c6mit, whereas glutamate caused a 70% decrease of this value. Subnanomolar ouabain exhibited immediate and postponed neuroprotective effects on neurons. (1) Ouabain rapidly reduced the Ca2+ overload of neurons and loss of \u03c6mit evoked by glutamate and HCY that rescued neurons in short insults. (2) In prolonged 24 h excitotoxic insults, ouabain prevented neuronal apoptosis, triggering proteinkinase A and proteinkinase C dependent intracellular neuroprotective cascades for HCY, but not for glutamate. We, therefore, demonstrated here the role of PKC and PKA involving pathways in neuronal survival caused by ouabain in hyperhomocysteinemia, which suggests existence of different appropriate pharmacological treatment for hyperhomocysteinemia and glutamate excitotoxicity.<\/jats:p>","DOI":"10.3390\/biom10081104","type":"journal-article","created":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T04:39:50Z","timestamp":1595824790000},"page":"1104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Calcium Export from Neurons and Multi-Kinase Signaling Cascades Contribute to Ouabain Neuroprotection in Hyperhomocysteinemia"],"prefix":"10.3390","volume":"10","author":[{"given":"Maria A.","family":"Ivanova","sequence":"first","affiliation":[{"name":"Laboratory of Comparative Neurophysiology, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arina D.","family":"Kokorina","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurophysiology, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Polina D.","family":"Timofeeva","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurophysiology, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana V.","family":"Karelina","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurophysiology, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-4527","authenticated-orcid":false,"given":"Polina A.","family":"Abushik","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurophysiology, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia D.","family":"Stepanenko","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurophysiology, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dmitry A.","family":"Sibarov","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurophysiology, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergei M.","family":"Antonov","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Neurophysiology, Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223 Saint-Petersburg, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1146\/annurev.med.49.1.31","article-title":"Homocysteine and cardiovascular disease","volume":"49","author":"Refsum","year":"1998","journal-title":"Annu. 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