Chemogenetic modulation in stroke recovery: A promising stroke therapy approach

Stroke remains a leading cause of long-term disability and mortality worldwide, necessitating novel therapeutic strategies to enhance recovery. Traditional rehabilitation approaches, including physical therapy and pharmacological interventions, often provide limited functional improvement. Neuromodulation has emerged as a promising strategy to promote post-stroke recovery by enhancing neuroplasticity and functional reorganization. Among various neuromodulatory techniques, chemogenetics, particularly Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), offers precise, cell-type-specific, and temporally controlled modulation of neuronal and glial activity. This review explores the mechanisms and therapeutic potential of chemogenetic modulation in stroke recovery. Preclinical studies have demonstrated that activation of excitatory DREADDs (hM3Dq) in neurons located within the peri-infarct area or contralateral M1 has been shown to enhance neuroplasticity, facilitate axonal sprouting, and lead to improved behavioral recovery following stroke. Conversely, stimulation of inhibitory DREADDs (hM4Di) suppresses stroke-induced excitotoxicity, mitigates peri-infarct spreading depolarizations (PIDs), and modulates neuroinflammatory responses. By targeting specific neuronal and glial populations, chemogenetics enables phase-specific interventions-early inhibition to minimize damage during the acute phase and late excitation to promote plasticity during the recovery phase. Despite its advantages over traditional neuromodulation techniques, such as optogenetics and deep brain stimulation, several challenges remain before chemogenetics can be translated into clinical applications. These include optimizing viral vector delivery, improving ligand specificity, minimizing off-target effects, and ensuring long-term receptor stability. Furthermore, integrating chemogenetics with existing stroke rehabilitation strategies, including brain-computer interfaces and physical therapy, may enhance functional recovery by facilitating adaptive neuroplasticity. Future research should focus on refining chemogenetic tools to enable clinical application. By offering a highly selective, reversible, and minimally invasive approach, chemogenetics holds great potential for revolutionizing post-stroke therapy and advancing personalized neuromodulation strategies.