Abstract
Status epilepticus (SE), a life-threatening neurologic emergency, is often poorly controlled by the current pharmacological therapeutics, which are limited to a narrow time window. Here, we investigated the proinflammatory cytokine high mobility group box-1 (HMGB1) as a candidate therapeutic target for diazepam (DZP)-refractory SE. We found that HMGB1 was upregulated and translocated rapidly during refractory SE period. Exogenous HMGB1 was sufficient to directly induce DZP-refractory SE in nonrefractory SE. Neutralization of HMGB1 with an anti-HMGB1 monoclonal antibody decreased the incidence of SE and alleviated the severity of seizure activity in DZP-refractory SE, which was mediated by a Toll-like receptor 4 (TLR4)-dependent pathway. Importantly, anti-HMGB1 mAb reversed DZP-refractory SE with a wide time window, extending the therapeutic window from 30 to 180 min. Furthermore, we found the upregulation of plasma HMGB1 level is closely correlated with the therapeutic response of anti-HMGB1 mAb in DZP-refractory SE. All these results indicated that HMGB1 is a potential therapeutic target and a useful predictive biomarker in DZP-refractory SE.
Original language | English |
---|---|
Pages (from-to) | 710-721 |
Number of pages | 12 |
Journal | Neurotherapeutics |
Volume | 17 |
Issue number | 2 |
DOIs | |
Publication status | Published - Apr 1 2020 |
Externally published | Yes |
Keywords
- HMGB1
- Status epilepticus
- anti-HMGB1 monoclonal antibody
- biomarker
- diazepam
- time window
ASJC Scopus subject areas
- Pharmacology
- Clinical Neurology
- Pharmacology (medical)