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Although physical activity (PA) may reduce this risk, it may not be feasible for all patients. Metformin, an anti-diabetic drug, has been proposed as an exercise mimetic due to its ability to reduce systemic inflammation. We investigated whether the voluntary wheel running (VWR) or metformin treatment (MF) impacts neuroinflammation of female mice following ovariectomy. Middle-aged (A) and young adult (Y) mice underwent ovariectomy (OVX) or sham operation (SHAM), and had access to VWR or MF in their drinking water for six weeks. A sedentary control group received water without metformin. The frontal cortex and serum samples were collected for further evaluation using western blot, RT-qPCR, and ELISA methods. Ovariectomy reduced running activity in both age groups. A decrease in NLRP3 expression was observed in middle-aged mice following PA. The NF-\u03baB p-p65\/p65 ratio increased in OVX\/MF_Y mice compared to SHAM\/MF_Y mice. Our results indicate a modulatory effect of running and metformin on neuroinflammation with varying effects that seem age-related and ovarian status-dependent. The responsiveness to PA and MF in the frontal cortex of adult mice could be mainly associated with the NF-\u03baB p65 signal.<\/jats:p>","DOI":"10.1038\/s41598-025-10014-0","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T04:46:54Z","timestamp":1753073214000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Age-dependent neuroinflammation response to voluntary wheel running and Metformin treatment in the frontal cortex of ovariectomized female mice"],"prefix":"10.1038","volume":"15","author":[{"given":"Konstancja","family":"Grabowska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mateusz","family":"Grabowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Morys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edyta","family":"Olakowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"Ma\u0142ecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaros\u0142aw J.","family":"Barski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Nowacka-Chmielewska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"10014_CR1","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.3233\/JAD-180141","volume":"64","author":"CR Beam","year":"2018","unstructured":"Beam, C. 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