High-concentration hydrogen mitigates cognitive impairment in a murine model of Sepsis-associated encephalopathy by enhancing oligodendrocyte maturation and myelination in the mPFC.

Sepsis-associated encephalopathy (SAE) commonly elicits long-lasting cognitive deterioration. Although hydrogen inhalation exerts protective effects in sepsis, its underlying mechanisms remain unclear. Dysregulated oligodendrocyte maturation and myelin architectural defects are pivotal pathological drivers of cognitive deficits across multiple neurological disorders. This study investigates whether high-concentration(67%) hydrogen gas protects against SAE by promoting oligodendrocyte maturation and myelination in the medial prefrontal cortex (mPFC). A CLP-induced mouse SAE model was established; mice received hydrogen inhalation at 1 and 4 h postoperatively plus daily 2-h sustained inhalation. To verify the underlying mechanism, mTOR agonist NV-5138 and antagonist rapamycin were used for pathway validation. The Morris water maze paradigm was adopted to quantify cognitive proficiency and conduct spatial training, which characterizes activity-dependent myelin remodeling. Western blotting, immunofluorescence staining, and transmission electron microscopy were performed to evaluate mTOR phosphorylation, oligodendrocyte maturation, and myelin integrity. The study indicated that mTOR hyperactivation in the medial prefrontal cortex of SAE mice impeded oligodendrocyte precursor cell differentiation, triggered hypomyelination, and ultimately precipitated cognitive dysfunction. 67% hydrogen inhalation markedly mitigated SAE-induced cognitive dysfunction by restraining mTOR overactivation to promote oligodendrocyte maturation and myelin reconstruction; rapamycin treatment exerted synergistic neuroprotective efficacy. Furthermore, SAE substantially abrogated spatial training-initiated myelin plasticity, whereas hydrogen therapy partially restored such brain adaptive capacity. In summary, hydrogen promotes oligodendrocyte maturation and myelination by suppressing mTOR pathway activity and restoring cortical myelin plasticity, thereby ameliorating cognitive dysfunction in SAE. This work reveals a previously unrecognized neuroprotective mechanism of hydrogen and provides actionable therapeutic targets for SAE clinical intervention.