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Our previous studies demonstrated Myelophil\u2019s clinical efficacy in ME\/CFS, as well as its brain-related activities in animal models. However, the underlying pharmacological mechanisms remain unclear. Recently, we identified serotonergic hyperactivity as a key pathophysiological factor in central fatigue, such as ME\/CFS. Therefore, in the present study, we aimed to investigate the mechanisms by which Myelophil exerts its effects, particularly in the context of a 5-HTergic hyperactivity model.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Method<\/jats:title>\n            <jats:p>To verify the action mechanisms of Myelophil on serotonergic hyperactivity condition, we herein assessed its anti-central fatigue properties using a fluoxetine-treated mice model. Male C57BL\/6\u00a0N mice (9 weeks old) were subjected to periodic intraperitoneal (IP) injections of fluoxetine for 4 weeks and the mice were simultaneously oral administered Myelophil (0, 50, or 100\u00a0mg\/kg) or ascorbic acid (100\u00a0mg\/kg).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Result<\/jats:title>\n            <jats:p>Four-week injection of fluoxetine notably increased serotonin (5-hydroxytryptamine, 5-HT) activity, as evidenced by immunofluorescence staining and Western blot assays in the raphe nuclei (RN), and induced central fatigue-like behaviors in the nest building test, wheel running test, rota-rod test, plantar test, and open field test. Meanwhile, Myelophil (100\u00a0mg\/kg) administration significantly ameliorated those fatigue-related behaviors including pain sensitivity. Furthermore, the anti-fatigue effects of Myelophil were corroborated by changes in serotonin-related parameters (serotonin transporter; 5-HTT and vesicular monoamine transporter 2; VMAT2), as well as neurotrophic markers including c-Fos and brain-derived neurotrophic factor (BDNF) in the RN.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>These results provide experimental evidence suggesting the potential mechanisms by which Myelophil may alleviate central fatigue associated with hyper-5-HTergic activity.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Clinical trial number<\/jats:title>\n            <jats:p>Not applicable.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12906-025-04882-2","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T15:15:37Z","timestamp":1745421337000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anti-central fatigue effects of myelophil in 5-HTergic hyperactivity mice model"],"prefix":"10.1186","volume":"25","author":[{"given":"Ji-Yun","family":"Kang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong-cheol","family":"Baek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin-Seok","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang-Gue","family":"Son","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"4882_CR1","doi-asserted-by":"crossref","unstructured":"Finsterer J, Mahjoub SZJAJH, Medicine\u00ae P. 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