{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:05:18Z","timestamp":1784009118677,"version":"3.55.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004242","name":"Princess Nourah Bint Abdulrahman University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004242","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Social isolation (SI), attributable to modern lifestyles and fast-growing technology, is a leading cause of depression. Selenium nanoparticles (Se-NPs) are neuroactive agents owing to their antioxidant and anti-inflammatory activities. Additionally, physical and mental activities (Ph&amp;amp;M) exert neuroprotective effects by optimizing the release of both neurotransmitters and growth factors. However, their neuroprotective effects against SI-induced depression are still poorly investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>We aim to explore the neuroprotective effect of Se-NPs, Ph&amp;amp;M, and their combination to guard against the harmful effects of SI-induced depression in a rat model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Fifty Sprague Dawley rats were randomly allocated into five groups: control, SI, Ph&amp;amp;M, orally administered Se-NPs (0.1\u00a0mg\/kg), and a combination group. Neuroprotective activity was quantitatively estimated pharmacologically, biochemically, histologically, and behaviorally.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SI caused behavioral and biochemical alteration in the rat model, decreasing neurotransmitter levels, increasing the transcription of inflammatory response genes (\n                      <jats:italic>TLR4<\/jats:italic>\n                      and\n                      <jats:italic>NF-\u03baB<\/jats:italic>\n                      ), and consequently increasing the production of the cytokines TNF-\u03b1 and IL-1\u03b2. It also activated the proinflammatory NLRP3\/caspase-1 pathway. The ER stress parameters PERK, CHOP, and GRP78 were significantly elevated. Impairment of autophagy and increased neurodegeneration were detected via the decline of AMPK\/SIRT-1\/Beclin-1 PI3K\/AKT gene expression and m-TOR overexpression. Decreased expression of TrkB and CREB mRNA and consequent decline in brain-derived neurotropic factor were recorded. SI caused a drastic drop in Wnt3a and \u03b2-catenin levels and increased GSK3\u03b2 activity affecting neuroplasticity and cognitive functions. Administration of Se-NPs and\/or application of Ph&amp;amp;M, especially their combination, provided significant protection against prior SI effects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Se-NPs and Ph&amp;amp;M, especially their combination, showed promising protective effects against neuroinflammation, oxidative stress, apoptosis and subsequent alterations of test animal behaviors precipitated by SI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1810142","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T05:37:41Z","timestamp":1784007461000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuroprotective potential of selenium nanoparticles and\/or physical and mental activities against social isolation\u2013induced depression in a rat model: inflammatory, oxidative stress, apoptotic, and neurotransmission modulatory pathways"],"prefix":"10.3389","volume":"17","author":[{"given":"Karema","family":"Abu-Elfotuh","sequence":"first","affiliation":[{"name":"Clinical Pharmacy Department, Faculty of Pharmacy (Girls), Al-Azhar University","place":["Cairo, Egypt"]},{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Al-Ayen Iraqi University, AUIQ","place":["An Nasiriyah, Iraq"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Furqan Hashim","family":"Hussein","sequence":"additional","affiliation":[{"name":"Collage of Dentistry, University of Alkafeel","place":["Kufa, Iraq"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roaa Hameed","family":"Alwaidh","sequence":"additional","affiliation":[{"name":"Department of Pathology and Forensic Medicine, Faculty of Medicine, University of Kufa","place":["Kufa, 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