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


CONCLUSIONS
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.
Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Yu
Y
Okuma
Keyue
K
Liu
Hidenori
H
Wake
Jiyong
J
Zhang
Tomoko
T
Maruo
Isao
I
Date
Tadashi
T
Yoshino
Aiji
A
Ohtsuka
Naoki
N
Otani
Satoshi
S
Tomura
Katsuji
K
Shima
Yasuhiko
Y
Yamamoto
Hiroshi
H
Yamamoto
Hideo K
HK
Takahashi
Shuji
S
Mori
Masahiro
M
Nishibori
D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005070:Evans Blue; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D017127:Glycation End Products, Advanced / Q000235:genetics; D005986:Glyceraldehyde 3-Phosphate / Q000378:metabolism; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D051195:Toll-Like Receptor 2 / Q000172:deficiency; D051197:Toll-Like Receptor 4 / Q000172:deficiency
D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D051793:Hypoxia-Inducible Factor 1; D007074:Immunoglobulin G; D008869:Microtubule-Associated Proteins; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D005986:Glyceraldehyde 3-Phosphate; D005070:Evans Blue; D011451:Prostaglandin-Endoperoxide Synthases