Abstract:

Ischemic stroke (IS) is one of the leading global causes of mortality and long-term disability. Its complex pathophysiology and the narrow therapeutic window for clinical intervention create urgent needs for advances in basic research and translational medicine. This review systematically summarizes the key pathological processes of IS, including excitotoxicity, oxidative stress, metabolic dysregulation, neuroinflammation, disruption of the neurovascular unit and blood–brain barrier, and the roles and interplay of multiple forms of programmed cell death (e.g., apoptosis, pyroptosis, ferroptosis, and the recently described PANoptosis) at different stages of cerebral injury, with emphasis on underlying molecular mechanisms. We compare commonly used animal models in terms of construction methods, applicable scenarios, and limitations—focusing on focal ischemia models such as middle cerebral artery occlusion (MCAO), thrombotic/photothrombotic models, microsphere embolization, and endothelin-1 models, as well as global cerebral ischemia models. Recent progress and challenges are reviewed for studies that incorporate the traditional Chinese medicine concept of "disease–syndrome integration" into model design and that evaluate interventions using herbal formulas or syndrome-based simulations. The review highlights the complementary strengths of integrative (East–West) research by defining syndrome groupings in animal models and combining multi-omics with network pharmacology, investigators can elucidate the multi-target, multi-pathway mechanisms by which Chinese medicines exert neuroprotective and reparative effects. Finally, we discuss future directions, including model standardization, gene-editing and humanized large-animal models, high-resolution imaging, single-cell and multi-omics analyses, artificial-intelligence–assisted data mining, and organoid/organ-on-chip platforms to optimize preclinical models and accelerate clinical translation, while underscoring the importance of ethical standards and reduction/replacement strategies. This review aims to provide a systematic reference and theoretical basis for mechanistic studies of IS, selection and refinement of animal models, translational research in integrative medicine, and the development of individualized precision rehabilitation strategies.

Key words: Ischemic stroke, Animal models, PANoptosis, Traditional Chinese and Western medicine, Model of combined disease and syndrome