Reassessment of Neuroprotective Efficacy of TUDCA in Ischemic Stroke: A Multi-Model In Vivo and In Vitro Study

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.