High mobility group box-1 (HMGB1) is a chromatin DNA-binding protein localized in nuclei. HMGB1, secreted or released from cells through cytosolic compartment by stress stimuli or injuries, exerts neurite outgrowth-promoting and pro-inflammatory activities. These features of HMGB1 on dynamics and biological activities are quite unique and distinct from those of known bioactive molecules. We raised anti-HMGB1 monoclonal antibody (mAb), validated the involvement of HMGB1 in different brain injuries and evaluated the efficacy of the mAb treatment. We found that the systemic injection of anti-HMGB1 mAb protected BBB disruption common to brain ischemia, hemorrhage, trauma and epilepsy, and reduced the inflammatory responses in the brain. We identified a plasma protein histidine-rich glycoprotein (HRG) as a HMGB1-binding protein. HRG plays a very important role in the homeostasis of blood cells, vascular endothelial cells and coagulation/fibrinolysis system. We proposed not only a novel hypothesis on septic cascade starting from a dramatic decrease in plasma HRG leading to immunothrombus formation but also a supplementary therapy with purified HRG. We identified CLEC1A as a novel receptor for HRG, and analyzed the regulation of HMGB1 mobilization by HRG. The translational research and drug development beginning with the target validation represent one of the directions in pharmacology.