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 microg, 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-alpha 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.

Glycyrrhizin attenuates rat ischemic spinal cord injury by suppressing inflammatory cytokines and HMGB1

“…HMGB1, as a mediator of postischemic brain damage, 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 treatment for this damage [23] . Intravenous injection of a neutralizing, anti-HMGB1 monoclonal antibody provides a novel therapeutic strategy for ischemic stroke [24] . In addition, serum HMGB1 levels were significantly elevated in patients with myocardial ischemia and cerebral ischemia, suggesting that systemic HMGB1 levels are elevated in human ischemic disease [25] .…”

Redox Regulation of Intracellular Zinc: Molecular Signaling in the Life and Death of Neurons

“…Other DAMPs may also contribute to microglia-mediated neurodegeneration after stroke. For example, the prototypical DAMP, highmobility group box 1 (HMGB1) is elevated in the serum of stroke patients (81), may be secreted from neurons triggering microglial activation (49), and contributes significantly to neurodegeneration after ischemia (69,81). Thus, further studies are needed to better understand the precise mechanisms by which immune cells and inflammatory signaling contributes to neurodegeneration after acute neuronal injury, as well as the relative roles of Zn 2þ in these processes.…”

HMGB1 contributes to allergen-induced airway remodeling in a murine model of chronic asthma by modulating airway inflammation and activating lung fibroblasts

“…More interestingly, HMGB1 has been shown to play a pivotal role in pulmonary fibrosis, partly through reduction of fibroblast proliferation and downregulation of interleukin (IL)-1b levels. 7 Furthermore, some researchers have found that HMGB1 promotes secretion of vascular endothelial growth factor (VEGF) 8 and that treatment with anti-HMGB1 antibodies suppresses the activity of matrix metalloproteinase (MMP)-9, 9 both of which are involved in airway remodeling.…”