Stroke-Related Animal Models: Methodologies, Applications, and Translational Perspectives

Stroke remains a leading cause of death and disability worldwide. Despite hundreds of neuroprotective agents showing promise in preclinical studies, nearly all have failed in clinical trials, largely due to inconsistencies between animal models and the human condition. This review provides a comprehensive overview of experimental stroke models, encompassing ischemic stroke (middle cerebral artery occlusion, photothrombosis, thromboembolic models, endothelin-1-induced vasoconstriction, global ischemia), hemorrhagic stroke (intracerebral hemorrhage, subarachnoid hemorrhage, epidural hematoma), cerebrovascular disease-related models (intracranial aneurysm, arteriovenous malformation), spontaneous stroke-prone models (hypertension, cerebral amyloid angiopathy), and special-condition models (neonatal hypoxic-ischemic encephalopathy, chronic cerebral hypoperfusion, post-stroke complications such as epilepsy, depression, dysphagia, and cognitive impairment). We systematically summarize the technical approaches, critical parameters, advantages, and limitations of each model, highlighting their applications in studying neuroprotection, reperfusion, hematoma expansion, inflammation, blood-brain barrier disruption, and rehabilitation strategies. In line with international guidelines such as STAIR and ARRIVE, we emphasize the importance of rigorous study design, including control of species, strain, sex, age, and comorbidities, as well as outcome measures aligned with clinical scenarios. Future directions include developing hybrid and comorbidity-integrated models to reflect the heterogeneity of human stroke, implementing cross-species validation, incorporating imaging and blood biomarkers into preclinical workflows, and advancing translational platforms for novel drugs and devices. Bridging the gap between animal modeling and clinical trial design will be crucial for accelerating the discovery of effective stroke therapies.