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This study investigates the anti-neuroinflammatory effects of three cardenolide derivatives, digitoxigenin, digitoxigenone, and coroglaucigenin (all at concentrations of 1, 5, 10, and 25 \u00b5M), in IL-1\u03b2-stimulated human neuroblastoma SK-N-SH cells. All compounds significantly reduced PGE2 production without affecting cell viability by downregulation of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthases (mPGES)-1 expression and synthesis. Among them, digitoxigenin notably inhibited phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-\u03baB) and suppressed interleukin (IL)-6 and IL-8 expression and release. These findings demonstrate that cardenolide derivatives exert potent anti-neuroinflammatory effects by at least partially targeting key enzymes of the arachidonic acid pathway and modulating MAPK\/NF-\u03baB signaling, highlighting their potential as novel therapeutic candidates for neuroinflammatory diseases. Future research should focus on effects of the cardenolides in mixed-cell cultures, organoids and in vivo experiments, to evaluate possible side effects and the potential in disease models.<\/jats:p>","DOI":"10.3390\/molecules31193501","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:19:08Z","timestamp":1790842748000},"page":"3501","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anti-Neuroinflammatory Effects of Cardenolides in IL-1\u03b2-Activated SK-N-SH Cells"],"prefix":"10.3390","volume":"31","author":[{"given":"Lu","family":"Sun","sequence":"first","affiliation":[{"name":"Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Matthias","family":"Apweiler","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany"},{"name":"Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Rami","family":"Schulzki","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0232-3279","authenticated-orcid":false,"given":"Christoph W.","family":"Grathwol","sequence":"additional","affiliation":[{"name":"Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Claus","family":"Normann","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-3191","authenticated-orcid":false,"given":"Stefan","family":"Br\u00e4se","sequence":"additional","affiliation":[{"name":"Institute of Biological and Chemical Systems-Functional Molecular Systems (IBCS-FMS), Karlsruhe Institute of Technology (KIT), Kaiserstrasse 12, 76131 Karlsruhe, Germany"},{"name":"Institute of Organic Chemistry, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9261-6771","authenticated-orcid":false,"given":"Bernd L.","family":"Fiebich","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Neurochemistry Research Group, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Twarowski, B., and Herbet, M. 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