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Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats

Keyue Liu^*,1, Shuji Mori^*,1,2, Hideo K. Takahashi^*, Yasuko Tomono, Hidenori Wake^*, Toru Kanke^*, Yasuharu Sato^*, Norihito Hiraga, Naoto Adachi, Tadashi Yoshino^* and Masahiro Nishibori^*,3

^* Departments of Pharmacology and Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan;

Shigei Medical Institute, Okayama, Japan; and

Department of Anesthesiology and Resuscitology, Ehime University, Graduate School of Medicine, Ehime, Japan

³Correspondence: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan. E-mail: mbori{at}md.okayama-u.ac.jp

The high mobility group box-1 (HMGB1), originally identified as an architectural nuclear protein, exhibits an inflammatory cytokine-like activity in the extracellular space. Here we show that treatment with neutralizing anti-HMGB1 monoclonal antibody (mAb; 200 µg, twice) remarkably ameliorated brain infarction induced by 2-h occlusion of the middle cerebral artery in rats, even when the mAb was administered after the start of reperfusion. Consistent with the 90% reduction in infarct size, the accompanying neurological deficits in locomotor function were significantly improved. Anti-HMGB1 mAb inhibited the increased permeability of the blood-brain barrier, the activation of microglia, the expression of TNF- and iNOS, and suppressed the activity of MMP-9, whereas it had little effect on blood flow. Intracerebroventricular injection of HMGB1 increased the severity of infarction. Immunohistochemical study revealed that HMGB1 immunoreactivity in the cell nuclei decreased or disappeared in the affected areas, suggesting the release of HMGB1 into the extracellular space. These results indicate that HMGB1 plays a critical role in the development of brain infarction through the amplification of plural inflammatory responses in the ischemic region and could be an outstandingly suitable target for the treatment. Intravenous injection of neutralizing anti-HMGB1 mAb provides a novel therapeutic strategy for ischemic stroke.—Liu, K., Mori, S., Takahashi, H. K., Tomono, Y., Wake, H., Kanke, T., Sato, Y., Hiraga, N., Adachi, N., Yoshino, T., Nishibori, M. Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats.

Key Words: target therapy • inflammation • blood-brain barrier • matrix metalloproteinase • inducible nitric oxide synthase