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

• Published in: Annals of neurology 2012-09, Vol.72 (3), p.373-384
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Biological and medical sciences; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - physiopathology; Brain damage; Brain Edema - etiology; Brain Edema - pathology; Brain Edema - prevention & control; Brain Injuries - drug therapy; Brain Injuries - pathology; Brain Injuries - physiopathology; Cell Death - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Evans Blue; Functional Laterality; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Glycation End Products, Advanced - genetics; Glyceraldehyde 3-Phosphate - metabolism; HMGB1 Protein - immunology; HMGB1 Protein - metabolism; HMGB1 Protein - pharmacology; Hypoxia-Inducible Factor 1 - metabolism; Immunoglobulin G - therapeutic use; Injuries of the nervous system and the skull. Diseases due to physical agents; Magnetic Resonance Imaging; Male; Medical sciences; Mice; Mice, Knockout; Microscopy, Electron, Transmission; Microtubule-Associated Proteins - metabolism; Motor Activity - drug effects; Neurology; Neurons - drug effects; Neurons - pathology; Neurons - ultrastructure; Prostaglandin-Endoperoxide Synthases - metabolism; Rats; Rats, Wistar; Rodents; Rotarod Performance Test; Toll-Like Receptor 2 - deficiency; Toll-Like Receptor 4 - deficiency; Traumas. Diseases due to physical agents
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.23602

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