Cell-based Therapies and Drug Repurposing in Stroke.

Abstract

Ischemic stroke is a leading cause of death and disability worldwide, and contributes substantially to the global burden of disease. Although reperfusion therapies such as intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) and mechanical thrombectomy have transformed acute management, the stringent eligibility criteria, narrow treatment windows, and limited accessibility restrict their use to <20% of patients. Many treated individuals have significant neurological deficits, and this underscores the urgent need for therapies that extend beyond revascularization. Two promising approaches have emerged: cell-based therapy and drug repurposing. Stem cell-based interventions, including mesenchymal stem cells, neural stem cells, and induced pluripotent stem cell-derived products, primarily act via paracrine mechanisms to modulate inflammation, attenuate oxidative stress, promote angiogenesis, and enhance neuroplasticity. Simultaneously, drug repurposing leverages the established safety and pharmacology of existing agents to accelerate clinical translation. Valproic acid, a histone deacetylase inhibitor, and perampanel, a selective AMPA receptor antagonist, target key mechanisms, such as excitotoxicity, oxidative injury, and epigenetic regulation. This review synthesizes the current evidence on both strategies and emphasizes mechanistic overlaps, clinical trial findings, translational barriers, and future directions. Unlike previous reviews that have addressed cell-based therapies or drug repurposing separately, we propose a unique phase-specific integrative framework that rationally combines these complementary strategies with reperfusion therapy and rehabilitation to achieve durable neuroprotection and meaningful recovery in ischemic stroke.