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 language | English |
|---|---|
| Pages (from-to) | 3904-3916 |
| Number of pages | 13 |
| Journal | FASEB Journal |
| Volume | 21 |
| Issue number | 14 |
| DOIs | |
| Publication status | Published - Dec 2007 |
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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 journal › Article
}
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 -