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Licochalcone A (LCA) has been described as an emerging anti-inflammatory drug with multiple therapeutical properties that could potentially prevent neurodegeneration. However, its neuroprotective mechanism remains unclear. Here, we investigated if LCA prevents cognitive decline induced by Lipopolysaccharide (LPS) and elucidated its potential benefits. For that, 8-week-old C57BL6\/J male mice were intraperitonially (i.p.) treated with saline solution or LCA (15\u00a0mg\/kg\/day, 3 times per week) for two weeks. The last day, a single i.p injection of LPS (1\u00a0mg\/kg) or saline solution was administered 24\u00a0h before sacrifice. The results revealed a significant reduction in mRNA expression in genes involved in oxidative stress (S<jats:italic>od1, Cat, Pkm, Pdha1, Ndyfv1, Uqcrb1, Cycs<\/jats:italic> and <jats:italic>Cox4i1),<\/jats:italic> metabolism<jats:italic> (Slc2a1, Slc2a2, Prkaa1<\/jats:italic> and <jats:italic>Gsk3b)<\/jats:italic> and synapsis (<jats:italic>Bdnf, Nrxn3<\/jats:italic> and <jats:italic>Nlgn2)<\/jats:italic> in LPS group compared to saline. These findings were linked to memory impairment and depressive-like behavior observed in this group. Interestingly, LCA protected against LPS alterations through its anti-inflammatory effect, reducing gliosis and regulating M1\/M2 markers. Moreover, LCA-treated animals showed a significant improvement of antioxidant mechanisms, such as citrate synthase activity and SOD2. Additionally, LCA demonstrated protection against metabolic disturbances, downregulating GLUT4 and P-AKT, and enhanced the expression of synaptic-related proteins (P-CREB, BDNF, PSD95, DBN1 and NLG3), leading all together to dendritic spine preservation. In conclusion, our results demonstrate that LCA treatment prevents LPS-induced cognitive decline by reducing inflammation, enhancing the antioxidant response, protecting against metabolic disruptions and improving synapsis related mechanisms.<\/jats:p>","DOI":"10.1186\/s10020-025-01106-8","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T01:23:11Z","timestamp":1739236991000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Licochalcone A prevents cognitive decline in a lipopolysaccharide-induced neuroinflammation mice model"],"prefix":"10.1186","volume":"31","author":[{"given":"Marina","family":"Carrasco","sequence":"first","affiliation":[]},{"given":"Laura","family":"Guzman","sequence":"additional","affiliation":[]},{"given":"Jordi","family":"Olloquequi","sequence":"additional","affiliation":[]},{"given":"Amanda","family":"Cano","sequence":"additional","affiliation":[]},{"given":"Ana","family":"Fortuna","sequence":"additional","affiliation":[]},{"given":"Manuel","family":"Vazquez-Carrera","sequence":"additional","affiliation":[]},{"given":"Ester","family":"Verdaguer","sequence":"additional","affiliation":[]},{"given":"Carme","family":"Auladell","sequence":"additional","affiliation":[]},{"given":"Miren","family":"Ettcheto","sequence":"additional","affiliation":[]},{"given":"Antoni","family":"Camins","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,2,11]]},"reference":[{"key":"1106_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/healthcare11212887","author":"H AlDehlawi","year":"2023","unstructured":"AlDehlawi H, Jazzar A. 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