Glial high-mobility group box 1 translocation promotes post-stroke epileptic seizures.

Post-stroke epilepsy (PSE) is a common type of epilepsy, often refractory to conventional pharmacological interventions. In the present study, we investigate the role of high mobility group box 1 (HMGB1) in PSE and evaluate therapeutic efficacy of the anti-HMGB1 monoclonal antibody therapy. We find that photothrombotic model of ischemic stroke enhanced seizure susceptibility, particularly in cases with extensive cortical lesions. Mechanistically, this vulnerability is driven by the nuclear-to-cytoplasmic translocation of HMGB1. Notably, the translocation rate in glial cells, rather than neurons, positively correlates with seizure severity. Treatment with an anti-HMGB1 monoclonal antibody not only markedly suppressed spontaneous seizures and pentylenetetrazol-induced susceptibility but also rescued cognitive deficits in PSE mice. These neuroprotective effects were mediated by the suppression of glial activation and the inhibition of HMGB1 translocation. Collectively, our findings identify glial HMGB1 translocation as a key driver of PSE and establish anti-HMGB1 therapy as a potent strategy for PSE intervention.