Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats

Jiyong Zhang, Hideo K. Takahashi, Keyue Liu, Hidenori Wake, Rui Liu, Tomoko Maruo, Isao Date, Tadashi Yoshino, Aiji Ohtsuka, Shuji Mori, Masahiro Nishibori

Research output: Contribution to journalArticle

176 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE-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.

Original languageEnglish
Pages (from-to)1420-1428
Number of pages9
JournalStroke
Volume42
Issue number5
DOIs
Publication statusPublished - May 2011

Fingerprint

Brain Ischemia
Blood-Brain Barrier
Monoclonal Antibodies
Middle Cerebral Artery Infarction
Brain Edema
Permeability
Endothelial Cells
Electrons
Brain Infarction
Pericytes
Tight Junctions
Brain
Extracellular Space
Basement Membrane
Intravenous Injections
Astrocytes
Ischemia
Immunoglobulin G
Observation
Cytokines

Keywords

  • blood- brain barrier
  • brain edema
  • electron microscopy
  • HMGB1
  • MRI

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialised Nursing

Cite this

Anti-high mobility group box-1 monoclonal antibody protects the blood-brain barrier from ischemia-induced disruption in rats. / Zhang, Jiyong; Takahashi, Hideo K.; Liu, Keyue; Wake, Hidenori; Liu, Rui; Maruo, Tomoko; Date, Isao; Yoshino, Tadashi; Ohtsuka, Aiji; Mori, Shuji; Nishibori, Masahiro.

In: Stroke, Vol. 42, No. 5, 05.2011, p. 1420-1428.

Research output: Contribution to journalArticle

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AU - Maruo, Tomoko

AU - Date, Isao

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KW - MRI

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