title: Alkoxyl radical-scavenging activity of edaravone in patients with traumatic brain injury.
abstract: Lipid peroxidation is caused by reactive oxygen species (ROS) and is involved in traumatic brain injury (TBI). Consequently, a therapeutic strategy for TBI may be to control lipid peroxidation. The only drug approved to date for blocking lipid peroxidation is edaravone (MCI-186), a novel free-radical scavenger shown to exert neuroprotective effects in acute ischemic stroke. Although edaravone scavenges hydroxyl and nitric oxide radicals, its effect on alkoxyl radicals (OR-), which also contribute to lipid peroxidation, is unknown. To date, the study of free radicals in blood has been severely hampered by technical difficulties in their detection. We used an in vitro and ex vivo electron spin resonance (ESR) method employing 5,5-dimethyl-1-pyrroline-N-oxide as a spin trap to investigate whether edaravone can scavenge OR-. By mixing either methemoglobin or human blood with tert-butyl hydroperoxide, we found that this technique can detect OR- generated in vitro. We also found that generated OR- can be completely absorbed by administration of edaravone in vitro (400 microM). Analysis of jugular venous blood collected from 17 TBI patients immediately before and 20 minutes after the administration of edaravone (30 mg, i.v.) revealed higher OR- levels in the untreated patients blood than in normal control blood samples. However, treatment with edaravone suppressed these OR- levels by 24.6% (radical intensity = 71.1 +/- 5.2-53.6 +/- 5.2; p < 0.01). Thus, edaravone can scavenge OR- and significantly reduce levels of these radicals in TBI patients. The novel ex vivo ESR method described here provides a valuable clinical measure of oxidative stress.
authors.affiliation: Department of Emergency and Critical Care Medicine, School of Medicine, Showa University, Tokyo, Japan. kdop@med.showa-u.ac.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Dohi
authors.forename: Kazue
authors.initials: K
authors.lastname: Satoh
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mihara
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakamura
authors.forename: Yasuhumi
authors.initials: Y
authors.lastname: Miyake
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohtaki
authors.forename: Tomoya
authors.initials: T
authors.lastname: Nakamachi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
authors.forename: Tohru
authors.initials: T
authors.lastname: Aruga
mesh_terms: D000328:Adult; D000438:Alcohols / Q000097:blood / Q000378:metabolism*; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001930:Brain Injuries / Q000097:blood* / Q000378:metabolism*; D000077553:Edaravone; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D019097:Spin Trapping / Q000379:methods*
chemical_list: D000438:Alcohols; D016166:Free Radical Scavengers; C059688:alkoxyl radical; D000077553:Edaravone; D000983:Antipyrine