Evidence of a role for spinal HMGB1 in ischemic stress-induced mechanical allodynia in mice.

Abstract

We have previously showed that spinal high-mobility group box-1 (HMGB1) plays an important role in the induction of central post-stroke pain (CPSP). It has been reported that HMGB1 exacerbates inflammation and pain via TLR4 or RAGE. Furthermore, the relationship between glial cells, such as microglia and astrocytes, involved in pain exacerbation and HMGB1 has also attracted attention. In this study, we investigated whether the interaction between spinal glial cells and HMGB1 signaling, including its receptors TLR4 or RAGE, is directly involved in the induction of CPSP. Spinal HMGB1 expression increased on day 3 after bilateral carotid artery occlusion (BCAO), and spinal microglia and astrocytes were clearly activated. HMGB1 colocalized with neurons, but not with microglia and astrocytes after BCAO. Intrathecal (i.t.) injection of lipopolysaccharides from Rhodobacter sphaeroides (LPS-RS, a TLR4 antagonist) and low-molecular-weight heparin (LMWH, a RAGE antagonist) significantly blocked mechanical allodynia on day 3 after BCAO. BCAO-induced activation of spinal microglia and astrocyte were suppressed by i.t. anti-HMGB1 monoclonal antibody (mAb) and LPS-RS administration. In addition, i.t. injection of NG-nitro-l-arginine methyl ester [a nonselective nitric oxide synthetase (NOS) inhibitor] significantly blocked mechanical allodynia on day 3 after BCAO and i.t. administration of anti-HMGB1 mAb, LPS-RS, and LMWH significantly inhibited the increase of NOS activity in the spinal cord on day 3 after BCAO. These results showed that the interaction between spinal glial cells and HMGB1/TLR4/NOS or HMGB1/RAGE/NOS is directly involved in the induction of CPSP.

• Authors: Wataru Matsuura, Shinichi Harada, Keyue Liu, Masahiro Nishibori, Shogo Tokuyama
• Journal: Brain research (Brain Res) Vol. 1687 Pg. 1-10 (05 15 2018) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 29476751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Aif1 protein, mouse
• Antibodies, Monoclonal
• Calcium-Binding Proteins
• Enzyme Inhibitors
• Glial Fibrillary Acidic Protein
• HMGB1 Protein
• Lipopolysaccharides
• Microfilament Proteins
• Receptor for Advanced Glycation End Products
• Toll-Like Receptor 4
• Nitric Oxide Synthase
• Phosphopyruvate Hydratase
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Brain Ischemia (complications, pathology)
• Calcium-Binding Proteins (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Glial Fibrillary Acidic Protein (metabolism)
• HMGB1 Protein (immunology, metabolism)
• Hyperalgesia (etiology, metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Mice
• Microfilament Proteins (metabolism)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Neuroglia (drug effects, metabolism)
• Nitric Oxide Synthase (metabolism)
• Phosphopyruvate Hydratase (metabolism)
• Physical Stimulation
• Receptor for Advanced Glycation End Products (metabolism)
• Spinal Cord (metabolism, pathology)
• Toll-Like Receptor 4 (metabolism)