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Hypothermia inhibits the propagation of acute ischemic injury by inhibiting HMGB1

 Jung Ho Lee  ;  Eun Jang Yoon  ;  Jeho Seo  ;  Adriana Kavoussi  ;  Yong Eun Chung  ;  Sung Phil Chung  ;  Incheol Park  ;  Chul Hoon Kim  ;  Je Sung You 
 MOLECULAR BRAIN, Vol.9 : 81, 2016 
Journal Title
Issue Date
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* ; Cytokines/metabolism ; Glycyrrhizic Acid/pharmacology ; HMGB1 Protein/antagonists & inhibitors* ; HMGB1 Protein/blood ; HMGB1 Protein/metabolism ; Hypothermia, Induced* ; Infarction, Middle Cerebral Artery/complications ; Infarction, Middle Cerebral Artery/pathology ; Inflammation Mediators/metabolism ; Injections, Intraventricular ; Male ; Nerve Tissue Proteins/metabolism ; Rats, Wistar
Acute ischemic stroke ; Glycyrrhizin ; High mobility group box 1 (HMGB1) ; Hypothermia ; Inflammatory cytokines ; Penumbra
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.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Emergency Medicine (응급의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
Kim, Chul Hoon(김철훈) ORCID logo https://orcid.org/0000-0002-7360-429X
Park, In Cheol(박인철) ORCID logo https://orcid.org/0000-0001-7033-766X
You, Je Sung(유제성) ORCID logo https://orcid.org/0000-0002-2074-6745
Lee, Jeong Ho(이정호)
Chung, Sung Pil(정성필) ORCID logo https://orcid.org/0000-0002-3074-011X
Chung, Yong Eun(정용은) ORCID logo https://orcid.org/0000-0003-0811-9578
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