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Taking into account that there is yet no satisfactory disease-modifying treatment, we investigated the effect of genistein on ouabain-induced BD in male C57BL\/6 mice. Animals were categorized into control, genistein control, ouabain model, lithium (Li)-treated, and genistein-treated groups. BD was induced by bilateral intracerebroventricular injection of 0.625 nmol ouabain. Genistein (10\u00a0mg\/kg\/day) was orally administered for 2 weeks following a single dose of ouabain. Open field test, sucrose preference test, and forced swim test were performed. Na\u207a\/K\u207a-ATPase activity was evaluated through measuring the hippocampal levels of phosphorylated epidermal growth factor receptor, proto-oncogene tyrosine-protein kinase, extracellular signal-regulated kinase, and cAMP response element-binding protein (p-CREB) by western blot analysis. The levels of brain-derived neurotrophic factor (BDNF), serotonin, oxidative stress, and inflammatory markers were quantified by ELISA. The BCL-2-associated X protein (BAX) to B-cell Lymphoma\/Leukemia (BCL2) ratio was assessed by qRT-PCR. Genistein reduced manic and anxious behaviors during the manic phase and showed an antidepressant effect during the depression phase, all while maintaining an effective metabolic balance on body weight. Additionally, genistein increased serotonin, p-CREB, and BDNF levels while decreasing inflammation and apoptosis produced by ouabain. Furthermore, genistein restored the normal architecture in both hippocampal and cortical H&amp;E-stained sections. Taken together, genistein was able to activate the Na\u207a\/K\u207a-ATPase signalosome via a multifaceted mode of action, exerting a neuroprotective effect in an animal model of BD, promoting genistein as a therapeutic candidate for BD.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>","DOI":"10.1007\/s11064-025-04597-3","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T03:57:59Z","timestamp":1765166279000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genistein Exerts Neuroprotective Effects in an Ouabain-Induced Model of Bipolar Disorder: Behavioral and Molecular Insights"],"prefix":"10.1007","volume":"51","author":[{"given":"Mariam T.","family":"Arafat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba R.","family":"Ghaiad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman M.","family":"Elbaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"4597_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2024.115953","author":"G L\u00e9da-R\u00eago","year":"2024","unstructured":"L\u00e9da-R\u00eago G, Studart-Bott\u00f3 P, Abbade P et al (2024) Lifetime prevalence of psychiatric comorbidities in patients with bipolar disorder: a systematic review and meta-analysis. 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