Edaravone protects against hypoxia/ischemia-induced endoplasmic reticulum dysfunction.
Endoplasmic reticulum (ER) stress-induced cell death plays an important role in cerebral ischemia. In the present study, we investigated whether edaravone (3-methyl-1-phenyl-pyrazolin-5-one), a free radical scavenger, can protect against ER damage induced by cerebral ischemia. In a mouse model of hypoxia/ischemia, treatment with edaravone reduced edema-corrected infarction volume, attenuated hemispheric swelling, and improved neurological status. Moreover, edaravone suppressed ER stress-mediated apoptosis by inhibiting eukaryotic initiation factor alpha phosphorylation, C/EBP homologous protein (CHOP) induction, and caspase-12 activation. In mouse primary cultured glial cells, edaravone attenuated ER stress as evidenced by inhibition of the induction of glucose regulated protein 78 and CHOP and XBP-1 splicing under treatment with tunicamycin (Tm), which induces ER stress. Tm did not induce the production of reactive oxygen species in primary cultured glial cells. In addition, the free radical scavengers N-acetyl-l-cysteine and ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] did not affect ER stress response caused by Tm. These results demonstrated a novel action of edaravone that can protect against ER dysfunction in cerebral ischemia.
Qi
Xin
X
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Okuma
Yasunobu
Y
Hosoi
Toru
T
Nomura
Yasuyuki
Y
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000209:etiology / Q000517:prevention & control*; D002478:Cells, Cultured; D000077553:Edaravone; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000473:pathology; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D000860:Hypoxia / Q000150:complications*; D007511:Ischemia / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000473:pathology; D014415:Tunicamycin / Q000494:pharmacology
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D014415:Tunicamycin; D000077553:Edaravone; D000983:Antipyrine