Hypothermia inhibits the propagation of acute ischemic injury by inhibiting HMGB1

• Published in: Molecular brain Vol. 9; no. 1; p. 81
• Main Authors: Lee, Jung Ho, Yoon, Eun Jang, Seo, Jeho, Kavoussi, Adriana, Chung, Yong Eun, Chung, Sung Phil, Park, Incheol, Kim, Chul Hoon, You, Je Sung
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.08.2016; BioMed Central
• Subjects: Acute Disease; Animals; Antibodies, Neutralizing - pharmacology; Antigens, Nuclear - metabolism; Brain Infarction - complications; Brain Infarction - pathology; Brain Ischemia - complications; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - therapy; Care and treatment; Complications and side effects; Cytokines - metabolism; Glycyrrhizic Acid - pharmacology; HMGB1 Protein - antagonists & inhibitors; HMGB1 Protein - blood; HMGB1 Protein - metabolism; Hypothermia; Hypothermia, Induced; Infarction, Middle Cerebral Artery - complications; Infarction, Middle Cerebral Artery - pathology; Inflammation Mediators - metabolism; Influence; Injections, Intraventricular; Interleukins; Male; Nerve Tissue Proteins - metabolism; Rats, Wistar; Risk factors; Stroke (Disease); Glycyrrhizin; Inflammatory cytokines; Penumbra; Acute ischemic stroke; High mobility group box 1 (HMGB1); Hypothermia
• ISSN: 1756-6606; 1756-6606
• DOI: 10.1186/s13041-016-0260-0

Acute ischemic stroke causes significant chronic disability worldwide. We designed this study to clarify the mechanism by which hypothermia helps alleviate acute ischemic stroke. In a middle cerebral artery occlusion model (4 h ischemia without reperfusion), hypothermia effectively reduces mean infarct volume. Hypothermia also prevents neurons in the infarct area from releasing high mobility group box 1 (HMGB1), the most well-studied damage-associated molecular pattern protein. By preventing its release, hypothermia also prevents the typical middle cerebral artery occlusion-induced increase in serum HMGB1. We also found that both glycyrrhizin-mediated inhibition of HMGB1 and intracerebroventricular neutralizing antibody treatments before middle cerebral artery occlusion onset diminish infarct volume. This suggests a clear neuroprotective effect of HMGB1 inhibition by hypothermia in the brain. We next used real-time polymerase chain reaction to measure the levels of pro-inflammatory cytokines in peri-infarct regions. Although middle cerebral artery occlusion increases the expression of interleukin-1β and tissue necrosis factor-α, this elevation is suppressed by both hypothermia and glycyrrhizin treatment. We show that hypothermia reduces the production of inflammatory cytokines and helps salvage peri-infarct regions from the propagation of ischemic injury via HMGB1 blockade. In addition to suggesting a potential mechanism for hypothermia's therapeutic effects, our results suggest HMGB1 modulation may lengthen the therapeutic window for stroke treatments.