This review discusses the use of animal models in the study of long-term functional recovery and rehabilitation after ischemic stroke, with an emphasis on processes beyond acute neuroprotection.
Review Article
This review discusses the use of animal models in the study of long-term functional recovery and rehabilitation after ischemic stroke, with an emphasis on processes beyond acute neuroprotection.
Ischemic stroke is one of the leading causes of long-term disability worldwide. Although acute neuroprotection strategies have been extensively studied, the mechanisms underlying long-term functional recovery after ischemic stroke remain incompletely understood. Animal models have played an important role in identifying key processes such as neural plasticity, angiogenesis, blood-brain barrier repair, and regulation of neuroinflammation during the recovery phase. These models enable the investigation of complex, time-dependent biological cascades that are difficult to examine directly in clinical studies. This narrative review discusses the application of animal models in studying long-term functional recovery after ischemic stroke. We highlight advances in understanding critical biological mechanisms, including axonal remodeling, neurogenesis, vascular repair, and immune modulation. Furthermore, we examine rehabilitation-oriented approaches evaluated in preclinical studies, such as stem cell therapy, neuromodulation techniques, pharmacological interventions, and environmental enrichment, and consider how mechanistic insights may inform their optimization. The integration of multimodal assessment methods-combining behavioral analyses, imaging, and molecular techniques-has strengthened the translational value of preclinical stroke recovery research. This narrative review provides a perspective on the development of mechanism-based rehabilitation strategies aimed at promoting sustained functional recovery beyond the acute phase of ischemic stroke. These insights help bridge the gap between preclinical research and clinical application and support improved outcomes for ischemic stroke survivors.
Ischemic stroke is a leading cause of disability worldwide and imposes a substantial burden on patients, families, and healthcare systems1,2,3. Despite advances in acute stroke therapies, including thrombolysis and mechanical thrombectomy, which have reduced mortality and limited initial brain injury, a considerable proportion of stroke survivors experience persistent long-term functional impairments4. These impairments commonly include motor deficits, cognitive dysfunction, and language disturbances, which severely reduce patients' autonomy and quality of life. Although acute therapies target early ischemic injury, their benefits during the chronic recovery phase remain limited, underscoring the need for interventions that promote neurological repair and long-term functional recovery beyond the acute stage5.
Traditionally, stroke research has focused on the acute neuroprotective window, intending to salvage penumbral tissue and reduce infarct size. However, this emphasis does not fully address the complex biological processes underlying long-term recovery, including neuroplasticity, neurogenesis, angiogenesis, and neural circuit remodeling6,7. The subacute and chronic phases of stroke involve dynamic interactions among neurons, glial cells, vascular components, and immune cells, which may contribute to spontaneous recovery or, conversely, to secondary degeneration and persistent disability8,9. Understanding these mechanisms is important for the development of therapies that enhance endogenous repair processes and optimize rehabilitation outcomes.
Compared with in vitro models or observational clinical studies alone, animal models offer distinct advantages for investigating these complex, system-level processes. They provide a controlled environment for longitudinal, mechanistic studies that are ethically and technically challenging to conduct in humans. Animal models have played a key role in elucidating the pathophysiology of ischemic stroke and in evaluating novel therapeutic strategies. Rodent models of middle cerebral artery occlusion (MCAO) and photothrombotic stroke reproduce multiple features of human ischemic injury and have provided valuable insights into the molecular and cellular mechanisms underlying injury and recovery10,11. These models allow detailed investigation of neurovascular remodeling, synaptic plasticity, and immune responses during the recovery process-phenomena that are difficult to examine directly in humans. Importantly, they also enable the controlled evaluation of rehabilitative interventions, pharmacological agents, and neuromodulatory techniques aimed at promoting long-term functional recovery12,13.
In addition to clarifying the biological mechanisms, animal models serve as valuable platforms for developing and refining rehabilitation strategies. For example, studies have reported that intensive, task-specific training can improve motor function after stroke, highlighting the importance of training intensity and timing during recovery14,15. Moreover, combining rehabilitative training with pharmacological agents, such as amphetamines or neurotrophic factors, has been reported to enhance neuroplasticity and motor recovery synergistically16,17. Noninvasive brain stimulation modalities, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have also shown promise in animal models for improving neurological and cognitive outcomes by modulating cortical excitability and promoting synaptic reorganization13,18.
Recent advances have broadened the scope of animal model research to include innovative therapeutic approaches, such as stem cell transplantation, gene therapy, and biomaterial scaffolds, which aim to replace lost neurons, modulate the post-stroke microenvironment, and support tissue regeneration19,20. For example, the transplantation of human cortically specified neuroepithelial progenitor cells has been reported to improve functional outcomes in mouse models, primarily through bystander effects rather than direct neuronal replacement21. Similarly, the delivery of neuroprotective circular RNAs and extracellular vesicles through novel administration routes has been associated with enhanced synaptic plasticity and vascular repair22,23.
Animal studies have contributed substantially to elucidating the roles of immune modulation and inflammation in stroke recovery. Activation of regulatory T cells and modulation of microglial phenotypes have emerged as potential therapeutic targets for fostering a pro-reparative environment and limiting secondary damage7,20. Pharmacological interventions targeting apoptosis, oxidative stress, and neuroinflammation have also been investigated, with some showing potential to promote endogenous neural precursor cell activation and improve long-term functional recovery24,25.
In addition to biological and pharmacological therapies, technological innovations, such as brain-computer interfaces, robot-assisted training, and virtual reality systems, have been developed and tested in animal models to augment traditional rehabilitation and facilitate motor relearning26,27. These approaches provide interactive, intensive training environments that can be adapted to individual deficits and support neuroplasticity.
Despite these advances, translating findings from animal models into clinical practice remains challenging because of species differences, variability in stroke pathology, and the complexity of human recovery processes. Incorporating comorbidities such as diabetes and hypertension into animal models has improved their clinical relevance and highlighted the influence of systemic factors on stroke outcomes and rehabilitation efficacy28,29. Moreover, the use of nonhuman primate models provides closer neuroanatomical and functional parallels to humans, enabling a more accurate assessment of motor deficits and therapeutic interventions30.
However, recognizing that animal models are not exact replicas of human stroke is important. Inherent limitations include species-specific differences in neuroanatomy, immune responses, lifespan, and the difficulty of fully modeling complex human comorbidities, social factors, and the extended time scale of recovery. These constraints necessitate cautious interpretation and extrapolation of preclinical findings to the clinical setting. Nonetheless, animal models are widely regarded as valuable tools for uncovering mechanisms of stroke recovery and informing rehabilitation strategies31. They offer a useful platform for investigating the multifaceted biological processes underlying long-term functional recovery, as well as for evaluating novel therapies that extend beyond acute neuroprotection. By linking basic science findings with clinical considerations, studies using animal models contribute to the development of targeted, mechanism-informed rehabilitation strategies that improve outcomes for stroke survivors. Although previous reviews have addressed animal models, recovery mechanisms, or rehabilitation strategies separately, this narrative review integrates these components to provide a focused perspective on the application of animal models in studying long-term functional recovery and rehabilitation after ischemic stroke, emphasizing key biological mechanisms and strategies that support recovery beyond the acute phase (Figure 1).
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Application of animal models in the study of long-term functional recovery after ischemic stroke
Common types of animal models and their characteristics
Animal models are widely used tools in ischemic stroke research, particularly for investigating long-term functional recovery. Rodent models, especially rats and mice, are predominantly utilized because of their cost-effectiveness, ease of genetic manipulation, and well-characterized physiology. The MCAO model, typically induced using an intraluminal filament, remains the most commonly used model for mimicking human ischemic stroke pathology. It allows precise control of reperfusion timing and is well-suited for studying focal ischemic injury and reperfusion mechanisms, although it does not fully reproduce the complexity of human stroke32. Embolic models, although less reproducible, are valuable for thrombolysis research33. Photothrombotic models enable the induction of targeted infarcts with consistent lesion sizes but often lack a reperfusion phase34. Nevertheless, the small brain size and lissencephalic cortex of rodents limit direct extrapolation to humans, especially regarding complex behaviors and neuroanatomical organization.
To address these limitations, large-animal models, including pigs, nonhuman primates, sheep, and dogs, have been developed. These species possess gyrencephalic brains that more closely resemble human cerebral anatomy and vasculature, making them more suitable for translational studies involving complex behaviors and neuroimaging35,36. For example, porcine models enable detailed gait analysis post-traumatic spinal cord injury, providing quantitative measures of functional recovery37. Nonhuman primates offer the closest approximation to human stroke pathophysiology; however, their use involves greater ethical, financial, and logistical considerations.
Model selection should consider the type of stroke (ischemic vs. hemorrhagic), lesion size, lesion location, and the intended recovery time window to ensure clinical relevance. Genetic models, including humanized hamsters with low-density lipoprotein receptor or ATP-binding cassette transporter A1 (ABCA1) knockouts, help elucidate stroke risk factors related to lipid metabolism38. Overall, no single model can reproduce all aspects of human stroke, necessitating the use of complementary models tailored to specific research questions to advance translational stroke research (Table 1).
Long-term functional assessment methods
Evaluating long-term functional recovery in animal models of stroke requires multidimensional approaches that include behavioral, imaging, and molecular analyses. Behavioral testing remains a central method for assessing motor coordination, sensory function, and cognitive abilities, and reflects the extent and quality of functional recovery. In rodent models, skilled reaching tasks, grid walking, cylinder tests, and rotarod performance are commonly used to quantify motor deficits and monitor recovery over weeks to months after stroke5,39. However, these tests have limitations, including the potential for compensatory behaviors, inter-rater variability, and, in some cases, insufficient sensitivity to subtle deficits40. For example, the skilled reaching task evaluates fine motor control and has been used to distinguish true recovery from compensatory movements7. Automated gait analysis systems provide objective and reproducible measures of locomotor function in models of peripheral and central nervous system injury41.
Neuroimaging modalities such as magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and magnetic resonance angiography (MRA) enable longitudinal monitoring of lesion evolution, cerebral blood flow, and neurovascular remodeling42,43. Positron emission tomography (PET) and functional MRI (fMRI) facilitate the assessment of neuronal network reorganization and changes in functional connectivity during recovery. MRI is well-suited for structural tracking, DWI for detecting acute injury, MRA for evaluating vasculature, PET for assessing metabolic activity, and fMRI for examining functional networks44. These imaging approaches can be correlated with behavioral outcomes to provide integrated insights into recovery mechanisms.
Research has also examined neurogenesis, synaptic plasticity, inflammation, and angiogenesis at both molecular and cellular levels. Expression of biomarkers such as neurofilament light chain (NFL), glial fibrillary acidic protein, and microRNAs has been assessed in animal models and human cohorts to elucidate recovery pathways and identify potential therapeutic targets8. These biomarkers may help distinguish true neural repair from compensatory adaptations45. Rehabilitation and pharmacological interventions can modulate neuroinflammatory responses and promote synaptic remodeling, processes that are important for functional recovery7,10. Electrophysiological assessments further complement these approaches by evaluating neuronal activity and network function.
Rigorous experimental design is crucial and includes the use of sham-operated controls, baseline behavioral assessments, blinding, randomization, and consideration of attrition46. Combining these methodologies enables robust evaluation of long-term recovery, helps distinguish true neural repair from compensatory adaptations, and supports assessment of therapeutic efficacy (Table 2).
Multimodal evaluation enhances translational value
Integrating behavioral, imaging, and molecular data through multimodal evaluation enhances the translational relevance of stroke recovery studies. Behavioral assessments provide functional endpoints, imaging captures structural and network-level changes, and molecular analyses reveal the underlying biological mechanisms. This comprehensive approach enables a more accurate characterization of recovery trajectories and therapeutic effects.
The application of high-throughput techniques, such as transcriptomics and proteomics, to stroke models has identified gene expression changes associated with neuroplasticity, inflammation, and repair10. These data support the identification of novel therapeutic targets and biomarkers that may predict recovery. For example, transcriptomic profiling has highlighted the involvement of the ubiquitin-proteasome system in neuronal survival post-ischemia, with compounds such as chlorogenic acid reported to modulate this pathway and provide neuroprotective effects10.
Furthermore, combining multimodal data can guide refinement of animal models to better reflect human stroke heterogeneity and recovery patterns, thereby helping to address translational gaps that limit the clinical success of neuroprotective strategies26. Advanced imaging in combination with behavioral testing allows monitoring of rehabilitation-induced neuroplasticity and functional reorganization, which may inform the timing and dosing of interventions47. Furthermore, integrating genetic and environmental factors into models may help predict individual variability in recovery25.
In summary, multimodal evaluation not only deepens mechanistic understanding but also improves the predictive value of preclinical studies, supporting the development of personalized rehabilitation strategies and facilitating translation into clinical practice.
Key biological mechanisms in long-term ischemic stroke recovery
Neuroplasticity and axonal regeneration
Neuroplasticity, which includes synaptic remodeling, axonal growth, and neural network reorganization, provides a biological basis for functional recovery after stroke. Animal studies have demonstrated that enhancing axonal regeneration and synapse formation can improve motor and cognitive outcomes after stroke. For example, interventions that promote axonal sprouting in peri-infarct regions facilitate the reestablishment of neural circuits critical for motor control, as evidenced by increased corticospinal tract connectivity and improved skilled forelimb performance in rodent models48. Several molecular pathways regulate these processes. Brain-derived neurotrophic factor (BDNF), acting through its receptor TrkB, promotes synaptic plasticity and axonal growth, whereas the mammalian target of rapamycin (mTOR) pathway modulates protein synthesis required for structural remodeling. Electroacupuncture studies in rats have reported that activation of mTOR signaling increases the expression of neuroplasticity-related proteins, such as GAP-43 and synaptophysin, thereby promoting corticospinal tract axon sprouting and functional recovery17. In stroke-injured mice, neural progenitor cell transplantation has also been associated with enhanced neuroplasticity partly through differentiation into mature neurons and graft-host molecular interactions involving neurexin and neuregulin signaling, which may support structural repair and long-term behavioral improvement16. Epigenetic regulation further contributes to these processes, since chromatin remodeling has been reported to influence transcriptional programs governing axon growth capacity and glial activation, thereby shaping neuroplastic responses17. Collectively, these findings highlight the importance of coordinated molecular and cellular mechanisms of neuroplasticity and axonal regeneration in supporting neurological function during the chronic phase after stroke.
Angiogenesis and blood - brain barrier (BBB) repair
Angiogenesis, the formation of new blood vessels, plays an important role in restoring cerebral blood flow to ischemic regions and supporting neuronal survival during stroke recovery. In animal models, increased angiogenesis has been associated with improved functional outcomes, likely because of enhanced oxygen and nutrient delivery to injured tissue. Although vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, its administration may increase BBB permeability and the risk of hemorrhage, which limits its clinical applicability49. Consequently, alternative strategies that target angiogenic pathways without compromising BBB integrity have been explored. For example, neutralization of the neurite growth-inhibitory factor Nogo-A has been reported to promote post-stroke angiogenesis while limiting vascular leakage, suggesting a potentially safer pro-angiogenic approach49. Other molecules have also been implicated in angiogenesis and BBB maintenance. Telomerase reverse transcriptase has been associated with enhanced angiogenesis and preservation of BBB integrity in neonatal hypoxic-ischemic brain injury models, possibly via Notch-1 signaling50. Additionally, zinc supplementation has been shown to enhance astrocyte-mediated VEGF secretion through the HIF-1α pathway, which may facilitate angiogenesis and neurological recovery in experimental stroke20. BBB repair is also a key component of post-stroke recovery. Endothelial peroxiredoxin-4 (Prx4) has been reported to support BBB integrity by modulating cytoskeletal dynamics and reducing inflammation, contributing to improved long-term neurological outcomes in ischemia-reperfusion models21. Furthermore, the deubiquitinase UCHL1 stabilizes Sox17 in endothelial cells, promoting angiogenesis and BBB restoration after spinal cord injury, highlighting the importance of post-translational regulation in vascular repair51. Collectively, these findings indicate that coordinated angiogenesis and BBB repair-regulated by multiple molecular pathways and cell types, including endothelial cells and astrocytes-play important roles in supporting functional recovery after stroke.
Regulation of neuroinflammation
Neuroinflammation plays a complex role in stroke recovery, with microglia and astrocytes contributing to both injury progression and tissue repair. Following an ischemic insult, these cells become activated and release pro-inflammatory cytokines that may exacerbate neuronal damage, while also participating in repair processes such as phagocytosis and secretion of neurotrophic factors. Animal studies have suggested that modulating the balance between pro- and anti-inflammatory states of microglia and macrophages is important for promoting neurogenesis, axonal regeneration, and functional recovery22. For example, interleukin-2 (IL-2) has been reported to promote polarization of microglia and macrophages toward an anti-inflammatory phenotype via inhibition of STAT3 phosphorylation, which is associated with enhanced white matter repair and improved neurological function after stroke22. Likewise, chrysophanol limits pro-inflammatory microglial activation and reduces IL-6-STAT3 signaling, thus supporting neuroplasticity and long-term recovery in ischemic mouse models23. Immune modulation strategies are increasingly investigated as potential therapeutic approaches; for instance, targeting the CD200-CD200R1 signaling pathway has been associated with reduced neuroinflammation and ischemic injury by promoting anti-inflammatory responses52. Epigenetic regulators, including EZH2 and microRNAs (e.g., miR-155), also influence microglial activation states and inflammatory gene expression, providing additional targets for modulating neuroinflammation53,54. Moreover, the gut microbiome has been linked to neuroinflammatory regulation and recovery, with microbiota-derived short-chain fatty acids such as acetate reported to promote angiogenesis and functional recovery in aged stroke models55. Collectively, these findings indicate that carefully modulating neuroinflammatory responses through cellular, molecular, and systemic mechanisms may help support long-term recovery after stroke. The key biological mechanisms involved in long-term stroke recovery, along with representative molecular players, associated functional outcomes, and corresponding therapeutic strategies identified in animal studies, are summarized in Table 3.
Individual variability and comorbidities
Individual differences in age, sex, and the presence of comorbidities can significantly influence stroke recovery trajectories and responses to therapy. These factors are increasingly incorporated into animal models to enhance translational relevance56. Aged animals typically show reduced neuroplasticity, impaired angiogenesis, and heightened neuroinflammatory responses compared with young adults, which are associated with poorer functional outcomes57. Sex differences have also been reported, with variations in inflammatory responses and neuroprotective mechanisms between males and females influencing recovery potential and treatment efficacy58. Common vascular comorbidities, such as hypertension and diabetes, can exacerbate ischemic injury, impair cerebrovascular function, and limit rehabilitation effectiveness. Animal models that incorporate these conditions (e.g., spontaneously hypertensive rats and diabetic mice) are valuable for evaluating rehabilitation strategies under clinically relevant circumstances59. Considering these variables in preclinical study design is important for developing more personalized rehabilitation approaches.
Key rehabilitation strategies
Preclinical evidence for long-term functional outcomes
Animal models have been widely used to assess long-term functional outcomes beyond motor deficits. Studies indicate that ischemic stroke can lead to persistent sensorimotor impairments, which can be quantified using the behavioral tests described above. Cognitive deficits affecting memory, learning, and executive function are also commonly observed in rodent models and are assessed using tasks such as the Morris water maze and novel object recognition60. In addition, post-stroke affective changes, including anxiety- and depressive-like behaviors, have been documented using paradigms such as the elevated plus maze and forced swim test61. These outcome measures highlight the multifaceted nature of stroke recovery and the importance of comprehensive rehabilitation strategies.
Stem cell therapy
Stem cell therapy has emerged as a promising rehabilitation strategy for promoting long-term functional recovery after stroke, primarily through mechanisms such as neuroregeneration, angiogenesis, and modulation of inflammation. Various types of stem cells-including mesenchymal stem cells (MSCs), neural stem cells (NSCs), hematopoietic stem cells, and induced pluripotent stem cells (iPSCs)-have been extensively studied in animal models, each with distinct therapeutic properties and mechanisms. MSCs derived from bone marrow, adipose tissue, or umbilical cord are often investigated because of their immunomodulatory properties, relative ease of isolation, and low immunogenicity, allowing them to influence post-stroke inflammation and secrete neurotrophic factors that support neuronal survival and vascular remodeling62,63. NSCs, sourced from fetal brain tissue or differentiated from pluripotent stem cells, may contribute to neural circuit repair by differentiating into neurons and glial cells, thereby supporting synaptic plasticity64. iPSCs offer the possibility of patient-specific therapies that may reduce immune rejection and have been explored for their capacity to differentiate into dopaminergic neurons and other neural lineages relevant to neurorestoration65,66.
Transplantation procedures, timing, and dosage are important parameters influencing therapeutic outcomes. Early transplantation during the subacute post-stroke phase has been associated with improved outcomes, potentially due to heightened brain plasticity, although delayed administration may also provide benefits by modulating chronic inflammation and promoting angiogenesis63,67. Delivery routes range from intracerebral to intraventricular injection, each involving trade-offs in invasiveness, cell engraftment, and distribution. Optimization of cell dose remains an area of investigation, aiming to balance therapeutic effects with potential risks such as tumorigenicity or ectopic tissue formation68. Moreover, stem cell-derived exosomes have gained attention as cell-free alternatives that carry bioactive molecules capable of reproducing some stem cell-mediated effects without the biosafety concerns associated with live cell transplantation69. Despite encouraging preclinical results, translation to clinical trials has yielded mixed results, reflecting challenges related to cell survival, integration, and standardization70. Collectively, animal studies underscore the diverse mechanisms through which stem cell-based approaches may support recovery, including secretion of neurotrophic factors, immunomodulation, angiogenesis, and, in some cases, cell replacement, providing a useful platform for translational research in stroke rehabilitation.
Neuromodulation techniques
Neuromodulation approaches, such as repetitive rTMS and electrical stimulation, have been increasingly investigated in animal models to enhance neural plasticity and support functional recovery after stroke. These noninvasive or minimally invasive methods modulate cortical excitability and facilitate the reorganization of neural networks involved in motor and cognitive functions. By delivering repetitive magnetic pulses, rTMS can increase or decrease neuronal activity depending on stimulation parameters, thereby influencing synaptic plasticity and cortical map reorganization11. Electrical stimulation modalities, including spinal cord stimulation and deep brain stimulation, have also been associated with modulation of neural circuits and improved motor recovery in preclinical stroke models9,12.
In animal studies, combining neuromodulation with behavioral training has been reported to improve motor function, suggesting that stimulation may prime neural substrates for experience-dependent plasticity13. Mechanistically, neuromodulation has been linked to enhanced synaptic efficacy, dendritic remodeling, and modulation of neurotransmitter systems, including glutamatergic and GABAergic signaling, which facilitate neural network reorganization14. Additionally, neuromodulation influences neuroinflammatory responses and neurovascular coupling, potentially contributing to a favorable environment for recovery. Emerging technologies, such as sonothermogenetics-which utilizes focused ultrasound to activate thermosensitive ion channels such as TRPV1-offer additional approaches for precise, noninvasive neuromodulation with potential therapeutic relevance24. Ongoing refinement of stimulation parameters and targeting strategies in animal models continues to inform clinical protocol development aimed at improving functional outcomes during stroke rehabilitation. However, variability in study results and challenges in replicating precise stimulation parameters remain important barriers to clinical translation71.
Pharmacological interventions and environmental enrichment
Pharmacological interventions targeting neurorepair mechanisms have shown potential to support post-stroke functional recovery in animal models. Neurotrophic factors, anti-inflammatory agents, and modulators of neurotransmitter systems have been evaluated for their roles in promoting neurogenesis, angiogenesis, and synaptic plasticity. For instance, drugs that upregulate BDNF expression or inhibit pro-inflammatory cytokines have been shown to improve motor and cognitive outcomes in preclinical studies12. Additionally, repurposed drugs with established safety profiles are being investigated to broaden therapeutic options for stroke recovery25.
Environmental enrichment (EE), defined by increased sensory, cognitive, and social stimulation, has been widely utilized in animal models as a non-pharmacological strategy to enhance neural plasticity and functional recovery. EE promotes experience-dependent synaptic remodeling, neurogenesis, and angiogenesis, which may contribute to improvements in motor and cognitive function72,73. EE has also been reported to increase the levels of neurotrophic factors such as BDNF and fibroblast growth factor receptors, which are involved in stem cell proliferation and neuronal differentiation74. Furthermore, EE can influence neuroinflammatory responses and support oligodendrocyte function, potentially contributing to remyelination and maintenance of neural circuit integrity5. Combining pharmacological treatments with EE may yield additive or synergistic effects that enhance rehabilitation outcomes12. Collectively, these approaches highlight the importance of multimodal strategies that integrate pharmacological and environmental factors to improve stroke recovery in animal models, with potential relevance for clinical rehabilitation. A comparative overview of the main rehabilitation strategies discussed, including their underlying mechanisms and supporting evidence from animal studies, is provided in Table 4.
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In conclusion, animal models are indispensable for elucidating the mechanisms of long-term functional recovery following ischemic stroke and for evaluating therapeutic strategies75. The integration of multimodal assessments within these models has significantly enhanced the rigor and translational potential of preclinical research4,76. This integrated framework is crucial for identifying therapeutic targets that might be missed in single-m...
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The authors have no conflicts of interest to disclose.
This work was supported by the Affiliated Hospital (Teaching Hospital) Research and Development Foundation of Shandong Second Medical University (No. 2024FYM048); the Shandong Province Medical Health Science and Technology Project (No. 202403071140); State Administration of Traditional Chinese Medicine Science and technology department co-construction of science and technology project (No.GZY-KJS-SD-2023-024) and Weifang Municipal Health Commission (No. WFWSJK-2025-009).
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