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Anti–high mobility group box‐1 antibody therapy for traumatic brain injury
Author(s) -
Okuma Yu,
Liu Keyue,
Wake Hidenori,
Zhang Jiyong,
Maruo Tomoko,
Date Isao,
Yoshino Tadashi,
Ohtsuka Aiji,
Otani Naoki,
Tomura Satoshi,
Shima Katsuji,
Yamamoto Yasuhiko,
Yamamoto Hiroshi,
Takahashi Hideo K.,
Mori Shuji,
Nishibori Masahiro
Publication year - 2012
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.23602
Subject(s) - hmgb1 , rage (emotion) , medicine , traumatic brain injury , blood–brain barrier , pharmacology , tlr4 , damp , receptor , advanced glycation end product , glycation , central nervous system , neuroscience , biology , physics , psychiatry , meteorology
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