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Current pharmacological treatments remain limited by incomplete efficacy and significant adverse effects, highlighting the need for novel therapeutic strategies. The present study investigated the neuroprotective effects of beta-caryophyllene (BCP), a natural sesquiterpene and selective cannabinoid receptor type 2 (CB2R) agonist, in a rat model of mania induced by intracerebroventricular ouabain (OUA) administration. Wistar rats received acute BCP treatment (three doses administered at 8-h intervals) starting one hour after OUA. Behavioral, biochemical, histological, and molecular analyses were performed seven days later. OUA induced manic-like behavioral alterations characterized by hyperactivity, increased risk-taking, and increased reactivity. These behavioral alterations were accompanied by increased lipid peroxidation, alterations in antioxidant enzyme activity, and enhanced neuronal degeneration in hippocampal regions, as indicated by Fluoro-Jade C staining. BCP treatment attenuated behavioral abnormalities, reduced oxidative damage, and prevented OUA-induced neuronal degeneration in the CA1, CA3, and dentate gyrus. Molecular analyses revealed that BCP restored phosphorylation of protein kinase A (PKA) and glycogen synthase kinase-3\u03b2 (GSK-3\u03b2), while reversing the reduction of nuclear factor erythroid-2-related factor 2 (NRF2) expression induced by OUA. Together, these findings support the hypothesis that modulation of redox homeostasis and changes in PKA\/GSK-3\u03b2\/NRF2 signaling may contribute to the neuroprotective and behavioral effects of BCP. These findings provide preclinical evidence supporting further investigation of BCP and the molecular mechanisms that may underlie its effects in experimental models relevant to BD.<\/jats:p>","DOI":"10.1007\/s11064-026-04843-2","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T15:29:30Z","timestamp":1784561370000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beta-Caryophyllene Prevents Ouabain-Induced Neurodegeneration and Behavioral Alterations Through PKA\/GSK-3\u03b2 Pathway"],"prefix":"10.1007","volume":"51","author":[{"given":"Jozy\u00ea Milena Silva","family":"Guerra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adson","family":"Souza-Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luan Machado","family":"Maidana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marizabel Parente","family":"Lins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel Lucca Martins","family":"Pereira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa Munir Mustafa","family":"Dahleh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Prigol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Fl\u00e1via","family":"Furian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro Schneider","family":"Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo Magno","family":"Rambo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"4843_CR1","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1001\/archgenpsychiatry.2011.12","volume":"68","author":"KR Merikangas","year":"2011","unstructured":"Merikangas KR, Jin R, He J-P, Kessler RC, Lee S, Sampson NA et al (2011) Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. 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