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Therefore, this study investigated the interactions between Na\u207a\/K\u207a-ATPase inhibition and PKC signaling, as well as the associated oxidative stress, using a translational approach that combines preclinical (in vitro and in vivo) models and clinical data from patients with bipolar disorder. In the in vitro model, cells were exposed to ouabain (OUA), a Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    ATPase inhibitor, and then treated with a PKC inhibitor (PKCi - tamoxifen). In the in vivo model, animals received intracerebroventricular OUA and were treated with PKCi. The animals underwent behavioral tests to evaluate manic- and depressive-like behaviors. The clinical study included a case-control protocol with 36 BD patients and 46 healthy controls. In both preclinical and clinical settings, the markers (4-hydroxynonenal [4-HNE], 8-isoprostane [8-ISO], thiobarbituric acid reactive substances [TBARS], carbonyl, and 3-nitrotyrosine [3-nitro]), as well as Na+\/K+ ATPase and PKC activities, were assessed. In the in vivo and in vitro protocols, OUA increased PKC activity and reduced Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    ATPase activity. However, when combined with PKCi, OUA failed to inhibit Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    ATPase activity. Additionally, OUA was able to induce manic- and depressive-like behaviors and oxidative stress, which was also reversed by PKCi. Moreover, the clinical protocol identified increased PKC activity and reduced Na+\/K+ ATPase activity, consistent with the preclinical protocols. Taken together, the data indicates that the interconnection between Na\u207a\/K\u207a-ATPase and PKC signaling pathways represents an important component of BD pathophysiology.\n                  <\/jats:p>","DOI":"10.1007\/s11064-026-04924-2","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T08:06:32Z","timestamp":1792656392000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interactions Between Na\u207a\/K\u207a-ATPase Inhibition and Protein Kinase C Signaling in Bipolar Disorder: Insights from Translational Data"],"prefix":"10.1007","volume":"51","author":[{"given":"Jorge M.","family":"Aguiar-Geraldo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeft\u00e9","family":"Peper-Nascimento","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taise","family":"Possamai-Della","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiani","family":"Daminelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tati\u00e9li","family":"Scheffer-Luiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vit\u00f3ria","family":"Bisognin-Ceretta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciane B.","family":"Ceretta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o","family":"Quevedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira S.","family":"Valvassori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,22]]},"reference":[{"key":"4924_CR1","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1590\/1516-4446-2012-1693","volume":"37","author":"AS Clemente","year":"2015","unstructured":"Clemente AS, Diniz BS, Nicolato R et al (2015) Bipolar disorder prevalence: a systematic review and meta-analysis of the literature. 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He also reports non-industry research support from Brigham and Women\u2019s Hospital, the John S. Dunn Foundation, and the National Network of Depression Centers. He has received consulting fees from LivaNova, EMS, and Libbs; speaker honoraria from Intra-Cellular Therapies, EMS, Libbs, Johnson & Johnson, Viatris, and GnTech; and royalties or copyright-related income from Grupo A\/Artmed and Elsevier\/Academic Press. All relationships are outside the submitted work.","order":1,"name":"Ethics","label":"Competing Interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"For clinical data: The Regional Ethics Committee, Comit\u00ea de \u00c9tica em Pesquisa e Humanos, approved the current study with the assigned protocol number 2,928,502. For preclinical data: This study was approved by the local ethics committee (Comiss\u00e3o de \u00c9tica no Uso de Animais da Universidade do Extremo Sul Catarinense - CEUA) under the protocol number 51\/2024.","order":2,"name":"Ethics","label":"Ethics Approval and Consent to Participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":3,"name":"Ethics","label":"Consent to Participate","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"304"}}