HMGB1 Is a Therapeutic Target and Biomarker in Diazepam-Refractory Status Epilepticus with Wide Time Window

Junli Zhao, Yang Zheng, Keyue Liu, Junzi Chen, Nanxi Lai, Fan Fei, Jiaying Shi, Cenglin Xu, Shuang Wang, Masahiro Nishibori, Yi Wang, Zhong Chen

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)710-721
Number of pages12
JournalNeurotherapeutics
Volume17
Issue number2
DOIs
Publication statusPublished - Apr 1 2020
Externally publishedYes

Keywords

  • HMGB1
  • Status epilepticus
  • anti-HMGB1 monoclonal antibody
  • biomarker
  • diazepam
  • time window

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

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  • Cite this

    Zhao, J., Zheng, Y., Liu, K., Chen, J., Lai, N., Fei, F., Shi, J., Xu, C., Wang, S., Nishibori, M., Wang, Y., & Chen, Z. (2020). HMGB1 Is a Therapeutic Target and Biomarker in Diazepam-Refractory Status Epilepticus with Wide Time Window. Neurotherapeutics, 17(2), 710-721. https://doi.org/10.1007/s13311-019-00815-3