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

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

Research output: Contribution to journalArticle

249 Citations (Scopus)

Abstract

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-α 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.

Original languageEnglish
Pages (from-to)3904-3916
Number of pages13
JournalFASEB Journal
Volume21
Issue number14
DOIs
Publication statusPublished - Dec 2007

Fingerprint

Brain Infarction
infarction
ischemia
Rats
monoclonal antibodies
Brain
Ischemia
Monoclonal Antibodies
Extracellular Space
brain
extracellular space
rats
Nuclear Proteins
Matrix Metalloproteinases
neutralization
Amplification
Blood
Middle Cerebral Artery Infarction
Chemical activation
Cells

Keywords

  • Blood-brain barrier
  • Inducible nitric oxide synthase
  • Inflammation
  • Matrix metalloproteinase
  • Target therapy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. / Liu, Keyue; Mori, Shuji; Takahashi, Hideo K.; Tomono, Yasuko; Wake, Hidenori; Kanke, Toru; Sato, Yasuharu; Hiraga, Norihito; Adachi, Naoto; Yoshino, Tadashi; Nishibori, Masahiro.

In: FASEB Journal, Vol. 21, No. 14, 12.2007, p. 3904-3916.

Research output: Contribution to journalArticle

Liu, Keyue ; Mori, Shuji ; Takahashi, Hideo K. ; Tomono, Yasuko ; Wake, Hidenori ; Kanke, Toru ; Sato, Yasuharu ; Hiraga, Norihito ; Adachi, Naoto ; Yoshino, Tadashi ; Nishibori, Masahiro. / Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. In: FASEB Journal. 2007 ; Vol. 21, No. 14. pp. 3904-3916.
@article{11e62d69c084413c94e81cca9b9dc6b5,
title = "Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats",
abstract = "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-α 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.",
keywords = "Blood-brain barrier, Inducible nitric oxide synthase, Inflammation, Matrix metalloproteinase, Target therapy",
author = "Keyue Liu and Shuji Mori and Takahashi, {Hideo K.} and Yasuko Tomono and Hidenori Wake and Toru Kanke and Yasuharu Sato and Norihito Hiraga and Naoto Adachi and Tadashi Yoshino and Masahiro Nishibori",
year = "2007",
month = "12",
doi = "10.1096/fj.07-8770com",
language = "English",
volume = "21",
pages = "3904--3916",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "14",

}

TY - JOUR

T1 - Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats

AU - Liu, Keyue

AU - Mori, Shuji

AU - Takahashi, Hideo K.

AU - Tomono, Yasuko

AU - Wake, Hidenori

AU - Kanke, Toru

AU - Sato, Yasuharu

AU - Hiraga, Norihito

AU - Adachi, Naoto

AU - Yoshino, Tadashi

AU - Nishibori, Masahiro

PY - 2007/12

Y1 - 2007/12

N2 - 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-α 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.

AB - 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-α 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.

KW - Blood-brain barrier

KW - Inducible nitric oxide synthase

KW - Inflammation

KW - Matrix metalloproteinase

KW - Target therapy

UR - http://www.scopus.com/inward/record.url?scp=36849076615&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36849076615&partnerID=8YFLogxK

U2 - 10.1096/fj.07-8770com

DO - 10.1096/fj.07-8770com

M3 - Article

C2 - 17628015

AN - SCOPUS:36849076615

VL - 21

SP - 3904

EP - 3916

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 14

ER -