{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T06:15:49Z","timestamp":1770963349810,"version":"3.50.1"},"reference-count":55,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003718","name":"KIOM","doi-asserted-by":"crossref","award":["KSN2225011"],"award-info":[{"award-number":["KSN2225011"]}],"id":[{"id":"10.13039\/501100003718","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>The efficacy of stigmasterol (STG) has not been previously evaluated in post-traumatic stress disorder (PTSD) models. Mice exposed to single prolonged stress with foot shock (SPS + FS) received oral STG (25 or 50 mg\/kg) for 14 days. Serum corticosterone and serotonin levels were measured, anxiety and cognition were assessed, synaptic plasticity-related proteins and genes were quantified, and neuronal nitric oxide synthase (nNOS), nitric oxide (NO) accumulation, nNOS-postsynaptic density protein 95 (PSD95), and nNOS-carboxy-terminal PDZ ligand of nNOS (CAPON) interactions were evaluated. STG significantly reduced serum corticosterone levels and increased serotonin levels altered by SPS+FS exposure. Behavioral analyses revealed attenuation of anxiety-like behavior and cognitive deficits. STG increased hippocampal synaptic plasticity-related proteins and genes and increased the number and maturation of doublecortin+ cells. Additionally, STG suppressed the PTSD-induced nNOS overactivation and NO accumulation in the hippocampus and serum, and altered nNOS-PSD95 and nNOS-CAPON associations in the hippocampus. Together, these findings provide integrated in vivo evidence suggesting that STG may influence stress-related neurobiological pathways relevant to PTSD.<\/jats:p>","DOI":"10.3390\/antiox15020238","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T17:45:36Z","timestamp":1770831936000},"page":"238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Stigmasterol Is Associated with Alterations in nNOS-PSD95\/CAPON Signaling and Synaptic Plasticity in a PTSD Model"],"prefix":"10.3390","volume":"15","author":[{"given":"Hee Ra","family":"Park","sequence":"first","affiliation":[{"name":"Department of KM Science Research, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mudan","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of KM Science Research, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun Jin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of KM Science Research, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseong-daero, Yuseong-gu, Daejeon 34054, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Aliev, G., Beeraka, N.M., Nikolenko, V.N., Svistunov, A.A., Rozhnova, T., Kostyuk, S., Cherkesov, I., Gavryushova, L.V., Chekhonatsky, A.A., and Mikhaleva, L.M. (2020). Neurophysiology and Psychopathology Underlying PTSD and Recent Insights into the PTSD Therapies-A Comprehensive Review. J. Clin. Med., 9.","DOI":"10.3390\/jcm9092951"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kmita, H., Pinna, G., and Lushchak, V.I. (2023). Potential oxidative stress related targets of mitochondria-focused therapy of PTSD. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1266575"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Perkovic, M.N., Milkovic, L., Uzun, S., Mimica, N., Pivac, N., Waeg, G., and Zarkovic, N. (2021). Association of Lipid Peroxidation Product 4-Hydroxynonenal with Post-Traumatic Stress Disorder. Biomolecules, 11.","DOI":"10.3390\/biom11091365"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.bbr.2016.06.016","article-title":"Amelioration of oxidative stress-induced phenotype loss of parvalbumin interneurons might contribute to the beneficial effects of environmental enrichment in a rat model of post-traumatic stress disorder","volume":"312","author":"Sun","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wilson, C.B., McLaughlin, L.D., Nair, A., Ebenezer, P.J., Dange, R., and Francis, J. (2013). Inflammation and oxidative stress are elevated in the brain, blood, and adrenal glands during the progression of post-traumatic stress disorder in a predator exposure animal model. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076146"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"117165","DOI":"10.1016\/j.jep.2023.117165","article-title":"Polysaccharides from Polygonatum cyrtonema Hua prevent post-traumatic stress disorder behaviors in mice: Mechanisms from the perspective of synaptic injury, oxidative stress, and neuroinflammation","volume":"319","author":"Xie","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"112266","DOI":"10.1016\/j.mce.2024.112266","article-title":"The role of nitric oxide and hormone signaling in chronic stress, anxiety, depression and post-traumatic stress disorder","volume":"590","author":"Jankovic","year":"2024","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e70201","DOI":"10.1002\/mnfr.70201","article-title":"Antidepressant-Like Effect of Saffron (Crocus sativus L.) in Mice Exposed to Chronic Unpredictable Mild Stress via Attenuating Neuroinflammation and Recovering Neuroplasticity","volume":"69","author":"Zhou","year":"2025","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.bbr.2019.02.044","article-title":"Effects of chronic mild stress induced depression on synaptic plasticity in mouse hippocampus","volume":"365","author":"Hei","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3656","DOI":"10.7150\/thno.70370","article-title":"Requirement of hippocampal DG nNOS-CAPON dissociation for the anxiolytic and antidepressant effects of fluoxetine","volume":"12","author":"Shi","year":"2022","journal-title":"Theranostics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.toxlet.2025.07.1411","article-title":"Nitric oxide plays a role in anxiety- and depression-like behaviors induced by sodium metabisulfite intake in rats","volume":"411","author":"Munzuroglu","year":"2025","journal-title":"Toxicol. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"114128","DOI":"10.1016\/j.bbr.2022.114128","article-title":"Neuronal nitric oxide synthase inhibition accelerated the removal of fluoxetine\u2019s anxiogenic activity in an animal model of PTSD","volume":"437","author":"Sadeghi","year":"2023","journal-title":"Behav. Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1111\/j.1471-4159.2007.04914.x","article-title":"Neuronal nitric oxide synthase contributes to chronic stress-induced depression by suppressing hippocampal neurogenesis","volume":"103","author":"Zhou","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1007\/s12264-023-01060-7","article-title":"nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story","volume":"39","author":"Zhu","year":"2023","journal-title":"Neurosci. Bull."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.ejphar.2011.11.050","article-title":"The ameliorating effects of stigmasterol on scopolamine-induced memory impairments in mice","volume":"676","author":"Park","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Pratiwi, R., Nantasenamat, C., Ruankham, W., Suwanjang, W., Prachayasittikul, V., Prachayasittikul, S., and Phopin, K. (2021). Mechanisms and Neuroprotective Activities of Stigmasterol Against Oxidative Stress-Induced Neuronal Cell Death via Sirtuin Family. Front. Nutr., 8.","DOI":"10.3389\/fnut.2021.648995"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"113317","DOI":"10.1016\/j.biopha.2022.113317","article-title":"Stigmasterol attenuates inflammatory response of microglia via NF-kappaB and NLRP3 signaling by AMPK activation","volume":"153","author":"Jie","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.2147\/NDT.S220224","article-title":"Stigmasterol Exerts Neuro-Protective Effect Against Ischemic\/Reperfusion Injury Through Reduction of Oxidative Stress and Inactivation of Autophagy","volume":"15","author":"Sun","year":"2019","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Souza, R.R., Noble, L.J., and McIntyre, C.K. (2017). Using the Single Prolonged Stress Model to Examine the Pathophysiology of PTSD. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00615"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1002\/9780470942390.mo140195","article-title":"Aging Research Using Mouse Models","volume":"5","author":"Anderson","year":"2015","journal-title":"Curr. Protoc. Mouse Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Selak, S., and Fritzler, M.J. (2004). Altered neurological function in mice immunized with early endosome antigen 1. BMC Neurosci., 5.","DOI":"10.1186\/1471-2202-5-2"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yanagisawa, D., Hamezah, H.S., Durani, L.W., Taguchi, H., and Tooyama, I. (2018). Study of tau pathology in male rTg4510 mice fed with a curcumin derivative Shiga-Y5. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0208440"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14722","DOI":"10.1038\/s41598-023-41996-4","article-title":"A quantitative analysis of spontaneous alternation behaviors on a Y-maze reveals adverse effects of acute social isolation on spatial working memory","volume":"13","author":"Kim","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1159\/000109862","article-title":"Doublecortin supports the development of dendritic arbors in primary hippocampal neurons","volume":"30","author":"Cohen","year":"2008","journal-title":"Dev. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/s41398-019-0477-7","article-title":"Chronic stress triggers divergent dendritic alterations in immature neurons of the adult hippocampus, depending on their ultimate terminal fields","volume":"9","author":"Dioli","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"524","DOI":"10.3390\/cimb45010035","article-title":"Single Prolonged Stress Decreases the Level of Adult Hippocampal Neurogenesis in C57BL\/6, but Not in House Mice","volume":"45","author":"Kurilova","year":"2023","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Plumpe, T., Ehninger, D., Steiner, B., Klempin, F., Jessberger, S., Brandt, M., Romer, B., Rodriguez, G.R., Kronenberg, G., and Kempermann, G. (2006). Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation. BMC Neurosci., 7.","DOI":"10.1186\/1471-2202-7-77"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5074","DOI":"10.3390\/ijms13045074","article-title":"Rhinacanthus nasutus extracts prevent glutamate and amyloid-beta neurotoxicity in HT-22 mouse hippocampal cells: Possible active compounds include lupeol, stigmasterol and beta-sitosterol","volume":"13","author":"Brimson","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1194\/jlr.M017244","article-title":"Dietary intake of plant sterols stably increases plant sterol levels in the murine brain","volume":"53","author":"Vanmierlo","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16072","DOI":"10.1523\/JNEUROSCI.1506-13.2013","article-title":"Plant sterols the better cholesterol in Alzheimer\u2019s disease? A mechanistical study","volume":"33","author":"Burg","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.intimp.2017.10.018","article-title":"Stigmasterol inhibits lipopolysaccharide-induced innate immune responses in murine models","volume":"53","author":"Antwi","year":"2017","journal-title":"Int. Immunopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3984068","DOI":"10.1155\/2018\/3984068","article-title":"Stigmasterol Alleviates Cutaneous Allergic Responses in Rodents","volume":"2018","author":"Antwi","year":"2018","journal-title":"Biomed. Res. Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"155225","DOI":"10.1016\/j.phymed.2023.155225","article-title":"Stigmasterol: Remodeling gut microbiota and suppressing tumor growth through Treg and CD8+ T cells in hepatocellular carcinoma","volume":"129","author":"Huo","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0014-2999(03)01272-X","article-title":"The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review","volume":"463","author":"Prut","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0149-7634(85)90030-2","article-title":"Exploratory behavior models of anxiety in mice","volume":"9","author":"Crawley","year":"1985","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3758\/s13415-024-01171-2","article-title":"Rodent tests of depression and anxiety: Construct validity and translational relevance","volume":"24","author":"Gencturk","year":"2024","journal-title":"Cogn. Affect. Behav. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17403","DOI":"10.1038\/s41598-019-53624-1","article-title":"Behavioural characterisation of chronic unpredictable stress based on ethologically relevant paradigms in rats","volume":"9","author":"Fornaguera","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"147147","DOI":"10.1016\/j.brainres.2020.147147","article-title":"Behavioral responses following repeated bilateral frontal region closed head impacts and fear conditioning in male and female mice","volume":"1750","author":"Vu","year":"2021","journal-title":"Brain Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/978-1-4939-8994-2_10","article-title":"The Y-Maze for Assessment of Spatial Working and Reference Memory in Mice","volume":"1916","author":"Kraeuter","year":"2019","journal-title":"Methods Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.neubiorev.2004.06.006","article-title":"The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory","volume":"28","author":"Hughes","year":"2004","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"101747","DOI":"10.1016\/j.cpr.2019.101747","article-title":"Posttraumatic stress disorder and neurocognition: A bidirectional relationship?","volume":"72","author":"Jacob","year":"2019","journal-title":"Clin. Psychol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"117243","DOI":"10.1016\/j.biopha.2024.117243","article-title":"Hominis Placenta modulates PTSD-like behaviors in SPSS-induced PTSD mice: Regulating energy metabolism and neuronal activity","volume":"178","author":"Cai","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Spinelli, S., Muller, T., Friedel, M., Sigrist, H., Lesch, K.P., Henkelman, M., Rudin, M., Seifritz, E., and Pryce, C.R. (2013). Effects of repeated adolescent stress and serotonin transporter gene partial knockout in mice on behaviors and brain structures relevant to major depression. Front. Behav. Neurosci., 7.","DOI":"10.3389\/fnbeh.2013.00215"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/s41398-019-0674-4","article-title":"Chronic corticosterone administration induces negative valence and impairs positive valence behaviors in mice","volume":"9","author":"Dieterich","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"117994","DOI":"10.1016\/j.ejmech.2025.117994","article-title":"Uncoupling toxic NO signaling: Progress, challenges, and therapeutic promise of disrupting the PSD-95\/nNOS protein-protein interaction","volume":"298","author":"Kamel","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Xie, W., Xing, N., Qu, J., Liu, D., and Pang, Q. (2023). The Physiological Function of nNOS-Associated CAPON Proteins and the Roles of CAPON in Diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115808"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41398-018-0208-5","article-title":"PSD95 and nNOS interaction as a novel molecular target to modulate conditioned fear: Relevance to PTSD","volume":"8","author":"Li","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7555\/JBR.34.20200108","article-title":"nNOS-mediated protein-protein interactions: Promising targets for treating neurological and neuropsychiatric disorders","volume":"35","author":"Gu","year":"2020","journal-title":"J. Biomed. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/aps.2009.67","article-title":"Nicotine and inflammatory neurological disorders","volume":"30","author":"Piao","year":"2009","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1126\/science.284.5421.1845","article-title":"Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein","volume":"284","author":"Sattler","year":"1999","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"115055","DOI":"10.1016\/j.envpol.2020.115055","article-title":"Involvement of NMDAR\/PSD-95\/nNOS-NO-cGMP pathway in embryonic exposure to BPA induced learning and memory dysfunction of rats","volume":"266","author":"Yu","year":"2020","journal-title":"Environ. Pollut."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.stemcr.2017.11.009","article-title":"GCN5 Regulates FGF Signaling and Activates Selective MYC Target Genes during Early Embryoid Body Differentiation","volume":"10","author":"Wang","year":"2018","journal-title":"Stem Cell Reports"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.bbr.2016.02.021","article-title":"Source memory in rats is impaired by an NMDA receptor antagonist but not by PSD95-nNOS protein-protein interaction inhibitors","volume":"305","author":"Smith","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12157","DOI":"10.1038\/srep12157","article-title":"Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ\/PSD-95-PDZ interactions","volume":"5","author":"Bach","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1038\/npp.2013.57","article-title":"Small-molecule inhibitors at the PSD-95\/nNOS interface have antidepressant-like properties in mice","volume":"38","author":"Doucet","year":"2013","journal-title":"Neuropsychopharmacology"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/2\/238\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T05:24:59Z","timestamp":1770960299000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/2\/238"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,11]]},"references-count":55,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["antiox15020238"],"URL":"https:\/\/doi.org\/10.3390\/antiox15020238","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,11]]}}}