Potent free radical scavenger, edaravone, suppresses oxidative stress-induced endothelial damage and early atherosclerosis.
OBJECTIVE
Effects of potent free radical scavenger, edaravone, on oxidative stress-induced endothelial damage and early atherosclerosis were investigated using animal models and cultured cells.


RESULTS
Endothelial apoptosis was induced by 5-min intra-arterial exposure of a rat carotid artery with 0.01 mmol/L H(2)O(2). Edaravone treatment (10mg/kg i.p.) for 3 days suppressed endothelial apoptosis, as evaluated by chromatin staining of en face specimens at 24h, by approximately 40%. Similarly, edaravone dose-dependently inhibited H(2)O(2)-induce apoptosis of cultured endothelial cells in parallel with the inhibition of 8-isoprostane formation, 4-hydroxy-2-nonenal (4-HNE) accumulation and VCAM-1 expression. Next, apolipoprotein-E knockout mice were fed a high-cholesterol diet for 4 weeks with edaravone (10mg/kg i.p.) or vehicle treatment. Edaravone treatment decreased atherosclerotic lesions in the aortic sinus (0.18+/-0.01 to 0.09+/-0.01 mm(2), P<0.001) and descending aorta (5.09+/-0.86 to 1.75+/-0.41 mm(2), P<0.05), as evaluated by oil red O staining without influence on plasma lipid concentrations or blood pressure. Dihydroethidium labeling and cytochrome c reduction assay showed that superoxide anions in the aorta were suppressed by edaravone. Also, plasma 8-isoprostane concentrations and aortic nitrotyrosine, 4-HNE and VCAM-1 contents were decreased by edaravone treatment.


CONCLUSIONS
These results suggest that edaravone may be a useful therapeutic tool for early atherosclerosis, pending the clinical efficacy.
Xi
Hang
H
Department of Geriatric Medicine, Kyorin University School of Medicine, Tokyo, Japan.
Akishita
Masahiro
M
Nagai
Kumiko
K
Yu
Wei
W
Hasegawa
Hiroshi
H
Eto
Masato
M
Kozaki
Koichi
K
Toba
Kenji
K
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D002791:Cholesterol, Dietary; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000077553:Edaravone; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology* / Q000627:therapeutic use; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000447:Aldehydes; D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D016166:Free Radical Scavengers; D016877:Oxidants; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; C075750:8-epi-prostaglandin F2alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D015237:Dinoprost; D006861:Hydrogen Peroxide; C027576:4-hydroxy-2-nonenal; D000077553:Edaravone; D000983:Antipyrine