Hindawi Publishing Corporation BioMed Research International Volume 2013, Article ID 379206, 13 pages http://dx.doi.org/10.1155/2013/379206 Research Article Therapeutic Time Window for Edaravone Treatment of Traumatic Brain Injury in Mice Kazuyuki Miyamoto, 1,2 Hirokazu Ohtaki, 1 Kenji Dohi, 2 Tomomi Tsumuraya, 1 Dandan Song, 1 Keisuke Kiriyama, 1 Kazue Satoh, 1 Ai Shimizu, 1 Tohru Aruga, 2 and Seiji Shioda 1 1 Department of Anatomy, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan 2 Department of Emergency and Critical Care Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan Correspondence should be addressed to Seiji Shioda; shioda@med.showa-u.ac.jp Received 5 January 2013; Revised 8 March 2013; Accepted 11 March 2013 Academic Editor: Norma Possa Marroni Copyright © 2013 Kazuyuki Miyamoto et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Traumatic brain injury (TBI) is a major cause of death and disability in young people. No efective therapy is available to ameliorate its damaging efects. Our aim was to investigate the optimal therapeutic time window of edaravone, a free radical scavenger which is currently used in Japan. We also determined the temporal profle of reactive oxygen species (ROS) production, oxidative stress, and neuronal death. Male C57Bl/6 mice were subjected to a controlled cortical impact (CCI). Edaravone (3.0mg/kg), or vehicle, was administered intravenously at 0, 3, or 6 hours following CCI. Te production of superoxide radicals ( 2 ∙− ) as a marker of ROS, of nitrotyrosine (NT) as an indicator of oxidative stress, and neuronal death were measured for 24 hours following CCI. Superoxide radical production was clearly evident 3 hours afer CCI, with oxidative stress and neuronal cell death becoming apparent afer 6 hours. Edaravone administration afer CCI resulted in a signifcant reduction in the injury volume and oxidative stress, particularly at the 3-hour time point. Moreover, the greatest decrease in  2 ∙− levels was observed when edaravone was administered 3 hours following CCI. Tese fndings suggest that edaravone could prove clinically useful to ameliorate the devastating efects of TBI. 1. Introduction In spite of the fact that traumatic brain injury (TBI) is a major cause of death and disability, particularly in young people, and given the huge socioeconomic costs of caring for afected persons, there is still no adequate treatment available to ameliorate its damaging efects [1, 2]. Te overall incidence of TBI in the United States is estimated to be 540 cases per 100,000 persons and the prevalence of long-term disability is estimated to be between 3.2 and 5.3 million. In 2000, the economic impact of TBI in the United States was estimated to be $9.2 billion in lifetime medical costs and $51.2 billion in lost productivity. Falls and motor vehicle accidents are the leading causes of TBI, with most cases transferred immediately to an emergency department [3]. Given that moderate and severe TBIs are associated with neurologic and functional impairments [4], further intensive care following initial treatment and diagnostic assessment are also usually required. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a derivative of antipyrin and was approved as free radical scavenger for the treatment of acute cerebral infarction in Japan [5]. Edaravone was frst reported to strongly scavenge hydroxyl radicals (OH − ) produced by the Fenton reaction in vitro and to decrease lipid and L-tyrosine oxidation [6]. Te efects of edaravone have been studied in relation to brain ischemia in animals and humans, and decreased brain edema, infarction, endothelial damage, and oxidative damage have been reported [6–11]. Edaravone has also been used in other neural injury models such as spinal cord injury [12], TBI [8, 13, 14], and brain hemorrhage [15] and was found to reduce lesion size and oxidative stress levels. We have previously