Anti-high mobility group box-1 antibody therapy for traumatic brain injury

Yu Okuma, Keyue Liu, Hidenori Wake, Jiyong Zhang, Tomoko Maruo, Isao Date, Tadashi Yoshino, Aiji Ohtsuka, Naoki Otani, Satoshi Tomura, Katsuji Shima, Yasuhiko Yamamoto, Hiroshi Yamamoto, Hideo K. Takahashi, Shuji Mori, Masahiro Nishibori

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

Objective: High mobility group box-1 (HMGB1) plays an important role in triggering inflammatory responses in many types of diseases. In this study, we examined the involvement of HMGB1 in traumatic brain injury (TBI) and evaluated the ability of intravenously administered neutralizing anti-HMGB1 monoclonal antibody (mAb) to attenuate brain injury. Methods: Traumatic brain injury was induced in rats or mice by fluid percussion. Anti-HMGB1 mAb or control mAb was administered intravenously after TBI. Results: Anti-HMGB1 mAb remarkably inhibited fluid percussion-induced brain edema in rats, as detected by T2-weighted magnetic resonance imaging; this was associated with inhibition of HMGB1 translocation, protection of blood-brain barrier (BBB) integrity, suppression of inflammatory molecule expression, and improvement of motor function. In contrast, intravenous injection of recombinant HMGB1 dose-dependently produced the opposite effects. Experiments using receptor for advanced glycation end product (RAGE)-/-, toll-like receptor-4 (TLR4)-/-, and TLR2-/- mice suggested the involvement of RAGE as the predominant receptor for HMGB1. Interpretation: Anti-HMGB1 mAb may provide a novel and effective therapy for TBI by protecting against BBB disruption and reducing the inflammatory responses induced by HMGB1. ANN NEUROL 2012;72:373-384

Original languageEnglish
Pages (from-to)373-384
Number of pages12
JournalAnnals of Neurology
Volume72
Issue number3
DOIs
Publication statusPublished - Sep 2012

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Okuma, Y., Liu, K., Wake, H., Zhang, J., Maruo, T., Date, I., Yoshino, T., Ohtsuka, A., Otani, N., Tomura, S., Shima, K., Yamamoto, Y., Yamamoto, H., Takahashi, H. K., Mori, S., & Nishibori, M. (2012). Anti-high mobility group box-1 antibody therapy for traumatic brain injury. Annals of Neurology, 72(3), 373-384. https://doi.org/10.1002/ana.23602