Early and Prolonged Cortical Electrical Stimulation Preserves Motor Functions and Nigrostriatal Dopaminergic Neurons in the MitoPark Model of Parkinson’s Disease

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder among the elderly. Although pharmacological therapies can alleviate symptoms, they often fail to provide sustained or complete symptom control, underscoring the need for alternative therapeutic strategies. Neuromodulation techniques, particularly cortical electrical stimulation (CES), have shown promise in modulating cortical plasticity. However, the therapeutic efficacy of CES in PD remains to be fully elucidated. In this study we investigated the long-term therapeutic potential of a novel CES protocol in a transgenic MitoPark mouse model of PD. Methods: MitoPark mice received CES beginning at 8 weeks of age (one session per day, 2 days per week) for a total of 12 weeks. Motor function was assessed using a comprehensive behavioral battery, including beam walking, open-field, and gait performance tests. Neuroprotective effects were evaluated by quantifying dopaminergic neuronal survival and striatal fiber density using tyrosine hydroxylase (TH) immunohistochemistry. Results: Long-term CES treatment significantly ameliorated motor impairments in MitoPark mice, improving locomotor activity, gait coordination, and beam walking performance compared with sham controls. Immunohistochemical analyses further revealed enhanced survival of nigrostriatal dopaminergic neurons and fibers in the CES-treated group, indicating pronounced neuroprotective effects. Conclusions: These findings demonstrate that early and sustained CES intervention mitigates motor deficits and enhances dopaminergic neuron survival in the MitoPark PD model. The results provide compelling preclinical evidence supporting CES as a potential adjunctive neuromodulatory therapy for Parkinson’s disease.