title: Hypothermia inhibits the propagation of acute ischemic injury by inhibiting HMGB1.
abstract: 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.
authors.affiliation: Department of Pharmacology, BK21 PLUS Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
authors.forename: Jung Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, BK21 PLUS Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
authors.forename: Eun Jang
authors.initials: EJ
authors.lastname: Yoon
authors.affiliation: Department of Pharmacology, BK21 PLUS Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
authors.forename: Jeho
authors.initials: J
authors.lastname: Seo
authors.affiliation: Department of Pharmacology, BK21 PLUS Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
authors.forename: Adriana
authors.initials: A
authors.lastname: Kavoussi
authors.affiliation: Department of Radiology, Yonsei University College of Medicine, Seoul, 03722, South Korea.
authors.forename: Yong Eun
authors.initials: YE
authors.lastname: Chung
authors.affiliation: Department of Emergency Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
authors.forename: Sung Phil
authors.initials: SP
authors.lastname: Chung
authors.affiliation: Department of Emergency Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea.
authors.forename: Incheol
authors.initials: I
authors.lastname: Park
authors.affiliation: Department of Pharmacology, BK21 PLUS Project for Medical Science, Brain Research Institute, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea. kimhoon@yuhs.ac.|Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea. kimhoon@yuhs.ac.
authors.forename: Chul Hoon
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Emergency Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, South Korea. youjsmd@yuhs.ac.
authors.forename: Je Sung
authors.initials: JS
authors.lastname: You
mesh_terms: D000208:Acute Disease; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D034961:Antigens, Nuclear / Q000378:metabolism; D020520:Brain Infarction / Q000150:complications / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D016207:Cytokines / Q000378:metabolism; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D007036:Hypothermia, Induced; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017208:Rats, Wistar
chemical_list: D057134:Antibodies, Neutralizing; D034961:Antigens, Nuclear; D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D009419:Nerve Tissue Proteins; C546339:Rbfox3 protein, rat; D019695:Glycyrrhizic Acid
keywords: Acute ischemic stroke; Glycyrrhizin; High mobility group box 1 (HMGB1); Hypothermia; Inflammatory cytokines; Penumbra