The free radical scavenger edaravone rescues rats from cerebral infarction by attenuating the release of high-mobility group box-1 in neuronal cells.
Edaravone, a potent free radical scavenger, is clinically used for the treatment of cerebral infarction in Japan. Here, we examined the effects of edaravone on the dynamics of high-mobility group box-1 (HMGB1), which is a key mediator of ischemic-induced brain damage, during a 48-h postischemia/reperfusion period in rats and in oxygen-glucose-deprived (OGD) PC12 cells. HMGB1 immunoreactivity was observed in both the cytoplasm and the periphery of cells in the cerebral infarction area 2 h after reperfusion. Intravenous administration of 3 and 6 mg/kg edaravone significantly inhibited nuclear translocation and HMGB1 release in the penumbra area and caused a 26.5 +/- 10.4 and 43.8 +/- 0.5% reduction, respectively, of the total infarct area at 24 h after reperfusion. Moreover, edaravone also decreased plasma HMGB1 levels. In vitro, edaravone dose-dependently (1-10 microM) suppressed OGD- and H(2)O(2)-induced HMGB1 release in PC12 cells. Furthermore, edaravone (3-30 microM) blocked HMGB1-triggered apoptosis in PC12 cells. Our findings suggest a novel neuroprotective mechanism for edaravone that abrogates the release of HMGB1.
Kikuchi
Kiyoshi
K
Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Department of Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Science, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
Kawahara
Ko-ichi
K
Tancharoen
Salunya
S
Matsuda
Fumiyo
F
Morimoto
Yoko
Y
Ito
Takashi
T
Biswas
Kamal Krishna
KK
Takenouchi
Kazunori
K
Miura
Naoki
N
Oyama
Yoko
Y
Nawa
Yuko
Y
Arimura
Noboru
N
Iwata
Masahiro
M
Tajima
Yutaka
Y
Kuramoto
Terukazu
T
Nakayama
Kenji
K
Shigemori
Minoru
M
Yoshida
Yoshihiro
Y
Hashiguchi
Teruto
T
Maruyama
Ikuro
I
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054022:Cerebrum / Q000378:metabolism / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D000077553:Edaravone; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D005947:Glucose / Q000172:deficiency; D024243:HMGB1 Protein / Q000097:blood / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D017208:Rats, Wistar; D009418:S100 Proteins / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D024243:HMGB1 Protein; D018696:Neuroprotective Agents; D009570:Nitriles; D009418:S100 Proteins; C113580:U 0126; D045304:Cytochromes c; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose; D000077553:Edaravone; D000983:Antipyrine