title: Edaravone attenuates white matter lesions through endothelial protection in a rat chronic hypoperfusion model.
abstract: A multicenter randomized clinical trial demonstrated that acute ischemic stroke patients treated with edaravone, a scavenger of hydroxyl radicals, had significant functional improvement. We tested the hypothesis that edaravone has protective effects against white matter lesions (WML) and endothelial injury, using a rat chronic hypoperfusion model. Adult Wistar rats underwent ligation of bilateral common carotid artery (LBCCA) and were divided into the edaravone group (injected once only immediately after LBCCA [n=39, ED(1)]; and injected on three consecutive days [n=39, ED(3)]), the vehicle group (n=39), and the sham group (n=15). Cerebral blood flow, Morris water maze performance, footprint test for locomotor function, immunohistochemical analyses and Western blot analysis were performed before and after LBCCA. The ED(3) group upregulated endothelial nitric oxide synthase and attenuated Evans Blue extravasation at day 3 after LBCCA (P<0.05). Edaravone markedly suppressed accumulation of 4-hydroxy-2-nonenal-modified protein and 8-hydroxy-deoxyguanosine (P<0.01), and loss of oligodendrocytes (P<0.05) in the cerebral white matter at days 3, 7, 14, 21 and 28 after LBCCA. These results were more evident in the ED(3) group. Moreover, at day 21 after LBCCA, spatial memory but not motor function, and axonal damage were significantly improved by three-time treatment of edaravone (P<0.05). Our results indicated that 3-day treatment with edaravone provides protection against WML through endothelial protection and free radical scavenging and suggested that edaravone is potentially useful for the treatment of cognitive impairment.
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ueno
authors.forename: N
authors.initials: N
authors.lastname: Zhang
authors.forename: N
authors.initials: N
authors.lastname: Miyamoto
authors.forename: R
authors.initials: R
authors.lastname: Tanaka
authors.forename: N
authors.initials: N
authors.lastname: Hattori
authors.forename: T
authors.initials: T
authors.lastname: Urabe
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D002908:Chronic Disease; D004249:DNA Damage / Q000187:drug effects; D000077553:Edaravone; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
chemical_list: D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D052250:Nitric Oxide Synthase Type III; D000077553:Edaravone; D000983:Antipyrine