{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:57:28Z","timestamp":1790686648973,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EraNet Neuron grant BiotaBB","award":["FNS N\u00b0 32NE30_213470"],"award-info":[{"award-number":["FNS N\u00b0 32NE30_213470"]}]},{"name":"TUBITAK Project","award":["N\u00b0 123N410"],"award-info":[{"award-number":["N\u00b0 123N410"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Ischemic stroke accounts for 87% of all strokes and remains a leading cause of mortality and morbidity worldwide, yet therapeutic options remain limited. Emerging evidence on the gut-brain axis and microbial metabolites as modulators of stroke outcome has positioned tauroursodeoxycholic acid (TUDCA), a taurine-conjugated secondary bile acid, as a candidate neuroprotective agent. Here, we evaluated the effects of intravenous TUDCA (100 mg\/kg) in male C57BL\/6 mice subjected to transient middle cerebral artery occlusion (tMCAO) or permanent distal middle cerebral artery occlusion (dMCAO), administered either one hour before or after stroke induction. Infarct size, neurological score, and IgG extravasation served as primary outcome measures, and blood-brain barrier (BBB) integrity was further assessed using a human iPSC-derived BBB organ-on-chip system. TUDCA did not significantly reduce infarct volume, improve neurological outcome, or attenuate BBB leakage in either in vivo model, nor did it preserve barrier permeability or ZO-1 expression in vitro under normoxic or hypoxic conditions. These findings indicate that, under the conditions tested, TUDCA does not influence the development of ischemic brain injury or features of BBB integrity, and that further optimization of dosing and administration strategies is required to fully evaluate its therapeutic potential in ischemic stroke.<\/jats:p>","DOI":"10.3390\/ijms27198702","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:09:25Z","timestamp":1790683765000},"page":"8702","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reassessment of Neuroprotective Efficacy of TUDCA in Ischemic Stroke: A Multi-Model In Vivo and In Vitro Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8472-5137","authenticated-orcid":false,"given":"Seyedeh Maryam","family":"Mousavi","sequence":"first","affiliation":[{"name":"Stroke Laboratory, Neurology Service, Department of Clinical Neurosciences, Lausanne University Hospital Centre, University of Lausanne, CH-1011 Lausanne, Switzerland"},{"name":"Department of Fundamental Neurosciences, University of Lausanne, CH-1005 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumeyra Nuran","family":"Ozmen","sequence":"additional","affiliation":[{"name":"Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla 34956, Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0317-050X","authenticated-orcid":false,"given":"Mujeeb Adekunle","family":"Adedokun","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU Medizin, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulin","family":"Baran","sequence":"additional","affiliation":[{"name":"Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla 34956, Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0518-5411","authenticated-orcid":false,"given":"Ahmet Baki","family":"Sahin","sequence":"additional","affiliation":[{"name":"Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla 34956, Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2921-5000","authenticated-orcid":false,"given":"Lorenz","family":"Hirt","sequence":"additional","affiliation":[{"name":"Stroke Laboratory, Neurology Service, Department of Clinical Neurosciences, Lausanne University Hospital Centre, University of Lausanne, CH-1011 Lausanne, Switzerland"},{"name":"Department of Fundamental Neurosciences, University of Lausanne, CH-1005 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8219-9399","authenticated-orcid":false,"given":"Nur","family":"Mustafaoglu","sequence":"additional","affiliation":[{"name":"Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla 34956, Istanbul, T\u00fcrkiye"},{"name":"Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, T\u00fcrkiye"},{"name":"Centre of Excellence for Functional Surfaces and Interfaces for Nano Diagnostics (EFSUN), Sabanci University, Tuzla 34956, Istanbul, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6463-7949","authenticated-orcid":false,"given":"Corinne","family":"Benakis","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU Medizin, LMU Munich, 81377 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.2174\/1389200216666151103115454","article-title":"Bile Acids in Physiology, Pathology and Pharmacology","volume":"17","author":"Marin","year":"2016","journal-title":"Curr. Drug Metab."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kusaczuk, M. (2019). Tauroursodeoxycholate\u2014Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives. Cells, 8.","DOI":"10.3390\/cells8121471"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"197","DOI":"10.4161\/pri.28938","article-title":"The Therapeutic Potential of Chemical Chaperones in Protein Folding Diseases","volume":"8","author":"Cortez","year":"2014","journal-title":"Prion"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"58","DOI":"10.7453\/gahmj.2014.017","article-title":"The Unexpected Uses of Urso- and Tauroursodeoxycholic Acid in the Treatment of Non-Liver Diseases","volume":"3","author":"Vang","year":"2014","journal-title":"Glob. Adv. Health Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Song, H., Liu, J., Wang, L., Hu, X., Li, J., Zhu, L., Pang, R., and Zhang, A. (2024). Tauroursodeoxycholic Acid: A Bile Acid That May Be Used for the Prevention and Treatment of Alzheimer\u2019s Disease. Front. Neurosci., 18.","DOI":"10.3389\/fnins.2024.1348844"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3727\/096020198389960","article-title":"Tauroursodeoxycholic Acid Improves the Survival and Function of Nigral Transplants in a Rat Model of Parkinson\u2019s Disease","volume":"11","author":"Duan","year":"2002","journal-title":"Cell Transplant."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1006\/exnr.2001.7755","article-title":"A Bile Acid Protects against Motor and Cognitive Deficits and Reduces Striatal Degeneration in the 3-Nitropropionic Acid Model of Huntington\u2019s Disease","volume":"171","author":"Keene","year":"2001","journal-title":"Exp. Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1097\/00004647-200204000-00010","article-title":"Neuroprotection by a Bile Acid in an Acute Stroke Model in the Rat","volume":"22","author":"Rodrigues","year":"2002","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6087","DOI":"10.1073\/pnas.1031632100","article-title":"Tauroursodeoxycholic Acid Reduces Apoptosis and Protects against Neurological Injury after Acute Hemorrhagic Stroke in Rats","volume":"100","author":"Rodrigues","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"119252","DOI":"10.1016\/j.lfs.2021.119252","article-title":"The Bile Acid TUDCA and Neurodegenerative Disorders: An Overview","volume":"272","author":"Zangerolamo","year":"2021","journal-title":"Life Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1177\/17474930241308142","article-title":"World Stroke Organization: Global Stroke Fact Sheet 2025","volume":"20","author":"Feigin","year":"2025","journal-title":"Int. J. Stroke Off. J. Int. Stroke Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3323","DOI":"10.1161\/STROKEAHA.110.608257","article-title":"Blood\u2013Brain Barrier Breakdown in Acute and Chronic Cerebrovascular Disease","volume":"42","author":"Yang","year":"2011","journal-title":"Stroke"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/sj.jcbfm.9600375","article-title":"Matrix Metalloproteinase-Mediated Disruption of Tight Junction Proteins in Cerebral Vessels Is Reversed by Synthetic Matrix Metalloproteinase Inhibitor in Focal Ischemia in Rat","volume":"27","author":"Yang","year":"2007","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lakhan, S.E., Kirchgessner, A., Tepper, D., and Aidan, L. (2013). Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke. Front. Neurol., 4, Erratum in Front. Neurol.\u00a02018, 9, 202. https:\/\/doi.org\/10.3389\/fneur.2018.00202.","DOI":"10.3389\/fneur.2018.00202"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1161\/STROKEAHA.122.036946","article-title":"Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities","volume":"53","author":"Dijkhuizen","year":"2022","journal-title":"Stroke"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.pneurobio.2017.10.001","article-title":"Blood-Brain Barrier Dysfunction and Recovery after Ischemic Stroke","volume":"163\u2013164","author":"Jiang","year":"2018","journal-title":"Prog. Neurobiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"C135","DOI":"10.1152\/ajpcell.00136.2018","article-title":"Neuroinflammatory Mechanisms of Blood-Brain Barrier Damage in Ischemic Stroke","volume":"316","author":"Yang","year":"2019","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/nm.4068","article-title":"Commensal Microbiota Affects Ischemic Stroke Outcome by Regulating Intestinal \u0393\u03b4 T Cells","volume":"22","author":"Benakis","year":"2016","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1161\/STROKEAHA.121.036800","article-title":"Gut Microbiota and Their Metabolites in Stroke: A Double-Edged Sword","volume":"53","author":"Peh","year":"2022","journal-title":"Stroke"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s40035-022-00307-z","article-title":"Tauroursodeoxycholic Acid: A Potential Therapeutic Tool in Neurodegenerative Diseases","volume":"11","author":"Khalaf","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"ar13","DOI":"10.1091\/mbc.E24-04-0147","article-title":"TUDCA Modulates Drug Bioavailability to Regulate Resistance to Acute ER Stress in Saccharomyces Cerevisiae","volume":"36","author":"Chadwick","year":"2025","journal-title":"Mol. Biol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Pasha, M., Kirschenman, R., Wooldridge, A., Spaans, F., Cooke, C.-L.M., and Davidge, S.T. (2023). The Effect of Tauroursodeoxycholic Acid (TUDCA) Treatment on Placental Endoplasmic Reticulum (ER) Stress in a Rat Model of Advanced Maternal Age. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0282442"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lavigna, G., Grasso, A., Pasini, C., Grande, V., Mignogna, L., Restelli, E., Masone, A., Fracasso, C., Lucchetti, J., and Gobbi, M. (2025). Trazodone, Dibenzoylmethane and Tauroursodeoxycholic Acid Do Not Prevent Motor Dysfunction and Neurodegeneration in Marinesco-Sj\u00f6gren Syndrome Mice. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0317404"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e4305","DOI":"10.21769\/BioProtoc.4305","article-title":"Transient Middle Cerebral Artery Occlusion with an Intraluminal Suture Enables Reproducible Induction of Ischemic Stroke in Mice","volume":"12","author":"Lemmerman","year":"2022","journal-title":"Bio-protocol"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/978-1-4939-0320-7_9","article-title":"A Mouse Model of Permanent Focal Ischemia: Distal Middle Cerebral Artery Occlusion","volume":"Volume 1135","author":"Milner","year":"2014","journal-title":"Cerebral Angiogenesis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1161\/01.STR.25.5.1075","article-title":"Prophylactic Neuroprotection for Cerebral Ischemia","volume":"25","author":"Fisher","year":"1994","journal-title":"Stroke"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1002\/1873-3468.15053","article-title":"A Guide for Blood\u2013Brain Barrier Models","volume":"599","author":"Soliman","year":"2025","journal-title":"FEBS Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1038\/s41467-019-10588-0","article-title":"Hypoxia-Enhanced Blood-Brain Barrier Chip Recapitulates Human Barrier Function and Shuttling of Drugs and Antibodies","volume":"10","author":"Park","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1161\/STROKEAHA.113.004075","article-title":"Found in Translation: Preclinical Stroke Research Predicts Human Pathophysiology, Clinical Phenotypes, and Therapeutic Outcomes","volume":"45","author":"Dirnagl","year":"2014","journal-title":"Stroke"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). The ARRIVE Guidelines 2.0: Updated Guidelines for Reporting Animal Research. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000410"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1186\/s13063-023-07638-w","article-title":"A Randomized Double-Blind Clinical Trial on Safety and Efficacy of Tauroursodeoxycholic Acid (TUDCA) as Add-on Treatment in Patients Affected by Amyotrophic Lateral Sclerosis (ALS): The Statistical Analysis Plan of TUDCA-ALS Trial","volume":"24","author":"Lombardo","year":"2023","journal-title":"Trials"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Gao, F., Guan, D., Wang, G., Zhang, L., He, J., Lv, W., Zhang, X., Tao, W., Dai, Y., and Xu, S. (2022). Effects of Oral Tauroursodeoxycholic Acid and\/or Intestinal Probiotics on Serum Biochemical Indexes and Bile Composition in Patients with Cholecystolithiasis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.882764"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1002\/ana.20741","article-title":"1,026 Experimental Treatments in Acute Stroke","volume":"59","author":"Macleod","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1038\/sj.jcbfm.9600298","article-title":"Bench to Bedside: The Quest for Quality in Experimental Stroke Research","volume":"26","author":"Dirnagl","year":"2006","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"149773","DOI":"10.1016\/j.brainres.2025.149773","article-title":"Tauroursodeoxycholic Acid Reduces Brain Lesion Volume and Cortical Edema in a Rat Model of Traumatic Brain Injury","volume":"1863","author":"Salazar","year":"2025","journal-title":"Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.neurobiolaging.2014.08.034","article-title":"Amyloid-\u03b2 Pathology Is Attenuated by Tauroursodeoxycholic Acid Treatment in APP\/PS1 Mice after Disease Onset","volume":"36","author":"Amaral","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1172\/JCI129401","article-title":"Bile acid metabolism is altered in multiple sclerosis and supplementation ameliorates neuroinflammation","volume":"130","author":"Bhargava","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/S1474-4422(15)00054-X","article-title":"Future Directions of Acute Ischaemic Stroke Therapy","volume":"14","author":"Fisher","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41582-021-00605-6","article-title":"Pharmacological Brain Cytoprotection in Acute Ischaemic Stroke\u2014Renewed Hope in the Reperfusion Era","volume":"18","author":"Fisher","year":"2022","journal-title":"Nat. Rev. Neurol."},{"key":"ref_40","first-page":"e54302","article-title":"Surgical Approach for Middle Cerebral Artery Occlusion and Reperfusion Induced Stroke in Mice","volume":"116","author":"Vital","year":"2016","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_41","first-page":"e51729","article-title":"Modeling Stroke in Mice: Permanent Coagulation of the Distal Middle Cerebral Artery","volume":"89","author":"Llovera","year":"2014","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7428","DOI":"10.1523\/JNEUROSCI.1114-16.2016","article-title":"Microbiota Dysbiosis Controls the Neuroinflammatory Response after Stroke","volume":"36","author":"Singh","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Buscemi, L., Price, M., Castillo-Gonz\u00e1lez, J., Chatton, J.-Y., and Hirt, L. (2022). Lactate Neuroprotection against Transient Ischemic Brain Injury in Mice Appears Independent of HCAR1 Activation. Metabolites, 12.","DOI":"10.3390\/metabo12050465"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/jcbfm.1990.47","article-title":"A Semiautomated Method for Measuring BrainInfarct Volume","volume":"10","author":"Swanson","year":"1990","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Mousavi, S.M., Buscemi, L., Castillo-Gonz\u00e1lez, J., Price, M., and Hirt, L. (2026). Exploration of the Preventive and Therapeutic Effects of D-Lactate Administration in a Mouse MCAO Model. Pharm. Basel Switz., 19.","DOI":"10.3390\/ph19030410"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.jneumeth.2011.01.010","article-title":"Long-Term Behavioral Assessment of Function in an Experimental Model for Ischemic Stroke","volume":"196","author":"Encarnacion","year":"2011","journal-title":"J. Neurosci. Methods"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1186\/s12974-023-02908-5","article-title":"Cortistatin Deficiency Reveals a Dysfunctional Brain Endothelium with Impaired Gene Pathways, Exacerbated Immune Activation, and Disrupted Barrier Integrity","volume":"20","author":"Ruiz","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1039\/b924816a","article-title":"Irreversible, Direct Bonding of Nanoporous Polymer Membranes to PDMS or Glass Microdevices","volume":"10","author":"Aran","year":"2010","journal-title":"Lab. Chip"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8702\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:14:17Z","timestamp":1790684057000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8702"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,29]]},"references-count":48,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198702"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198702","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,29]]}}}