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The objective of this study is to assess the potential of isorhmanetin, known for its anti-inflammatory and antidepressant properties, in mitigating these behaviors in male mice. The experimental mice underwent a 4-h daily maternal separation from postnatal days 2 to 21. Afterwards, mice were given an intraperitoneal injection of isorhamnetin (20\u00a0mg\/kg\/day) from postnatal day 61 for 4\u00a0weeks. At 3\u00a0months old, both behavioral evaluations and biochemical analyses were carried out. The findings indicated that the isolated mice displayed clear signs of anxiety and depression-like behaviors, along with increased levels of various cytokines (IL-1\u03b2, IL-6, and TNF-\u03b1) in the hippocampus and decreased levels of Sirt1, accompanied by elevated NF-\u03baB p65 expression. The effects were mitigated by treatment with isorhamnetin, resulting in the normalization of behavior and cytokine levels, as well as the activation\u00a0of Sirt1 expression in addition to downregulation of\u00a0NF-\u03baB p65. Isorhamnetin has the potential to be utilized as a treatment for anxiety and depression-like symptoms by adjusting pathways of neuroinflammation and the signaling axis of Sirt1 and NF-\u03baB. This opens the door for further investigation in mitigating the biochemical and behavioral adverse effects induced by separation during the maternal period.<\/jats:p>","DOI":"10.1007\/s12035-025-05483-3","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T11:16:30Z","timestamp":1764414990000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Isorhamnetin Alleviates Early-Life Stress-Induced Anxiety and Depression in Male Mice: Neuroinflammatory Modulation and Sirt1\/NF-\u03baB Signaling Insights"],"prefix":"10.1007","volume":"63","author":[{"given":"Esam","family":"Qnais","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Gammoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Alqudah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal","family":"Al-Bzour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Wedyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelrahim","family":"Alqudah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anwar M.","family":"Alnakhli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sireen Abdul Rahim","family":"Shilbayeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa A. 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