Methylprednisolone Restores Cognitive Impairment in mdx Mice by Inhibiting NF-κB/CCL5-mediated Neuroinflammation

Duchenne muscular dystrophy (DMD) is an X-linked recessive hereditary neuromuscular disease. In addition to movement disorders such as muscle weakness, it can also show varying degrees of cognitive impairment and behavioral problems. While glucocorticoids are the first-line treatment for DMD, their effects on cognitive function remain unclear. This study aims to investigate whether glucocorticoid therapy can improve cognitive impairments in DMD and to explore the potential underlying mechanisms. The study utilized mdx mice as an animal model, administering 6α-methylprednisolone (MP) via intraperitoneal injection for five weeks (1 mg/kg/day). The effects of MP on cognition and synaptic plasticity were assessed through behavioral tests, electrophysiology, Western blotting, and Golgi staining. Additionally, transcriptomic sequencing was performed to analyze the impact of MP on gene expression profiles in mdx mice. MP intervention ameliorated cognitive dysfunction in mdx mice, restored synaptic protein expression (Dp71, GABRA2, and PSD-95), increased dendritic spine density, enhanced dendritic complexity, and normalized abnormally enhanced long-term potentiation. Transcriptomic analysis revealed that neuroinflammation is present in the mdx brain; MP intervention alleviated neuroinflammation by inhibiting the NF-κB/CCL5 pathway, thereby improving synaptic plasticity. This research systematically demonstrates that glucocorticoids can mitigate cognitive impairments in DMD by inhibiting the NF-κB/CCL5 signaling pathway. These findings expand the theoretical framework for using glucocorticoids to treat central nervous system damage in DMD and suggest that targeting this pathway may represent a novel strategy for cognitive protection.