title: Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats.
abstract: OBJECTIVE
  High mobility group box-1 (HMGB1) exhibits inflammatory cytokine-like activity in the extracellular space. We previously demonstrated that intravenous injection of anti-HMGB1 monoclonal antibody (mAb) remarkably ameliorated brain infarction induced by middle cerebral artery occlusion in rats. In the present study, we focused on the protective effects of the mAb on the marked translocation of HMGB1 in the brain, the disruption of the blood-brain barrier (BBB), and the resultant brain edema.
  
  
  METHODS
  Middle cerebral artery occlusion in the rat was used as the ischemia model. Rats were treated with anti-HMGB1 mAb or control IgG intravenously. BBB permeability was measured by MRI. Ultrastructure of the BBB unit was observed by transmission electron microscope. The in vitro BBB system was used to study the direct effects of HMGB1 in BBB components.
  
  
  RESULTS
  HMGB1 was time-dependently translocated and released from neurons in the ischemic rat brain. The mAb reduced the edematous area on T2-weighted MRI. Transmission electron microscope observation revealed that the mAb strongly inhibited astrocyte end feet swelling, the end feet detachment from the basement membrane, and the opening of the tight junction between endothelial cells. In the in vitro reconstituted BBB system, recombinant HMGB1 increased the permeability of the BBB with morphological changes in endothelial cells and pericytes, which were inhibited by the mAb. Moreover, the anti-HMGB1 mAb facilitated the clearance of serum HMGB1.
  
  
  CONCLUSIONS
  These results indicated that the anti-HMGB1 mAb could be an effective therapy for brain ischemia by inhibiting the development of brain edema through the protection of the BBB and the efficient clearance of circulating HMGB1.
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmacological Sciences, Okayama 700-8558, Japan.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhang
authors.forename: Hideo K
authors.initials: HK
authors.lastname: Takahashi
authors.forename: Keyue
authors.initials: K
authors.lastname: Liu
authors.forename: Hidenori
authors.initials: H
authors.lastname: Wake
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Tomoko
authors.initials: T
authors.lastname: Maruo
authors.forename: Isao
authors.initials: I
authors.lastname: Date
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Aiji
authors.initials: A
authors.lastname: Ohtsuka
authors.forename: Shuji
authors.initials: S
authors.lastname: Mori
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D001929:Brain Edema / Q000503:physiopathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D024243:HMGB1 Protein / Q000276:immunology* / Q000378:metabolism; D016756:Immunoglobulins, Intravenous; D020244:Infarction, Middle Cerebral Artery; D008279:Magnetic Resonance Imaging; D008297:Male; D046529:Microscopy, Electron, Transmission; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D016756:Immunoglobulins, Intravenous