Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain

Background and Purpose - Oxidative stress contributes to ischemia/reperfusion neuronal damage in a consecutive 2-phase pattern: an immediate direct cytotoxic effect and subsequent redox-mediated inflammatory insult. The present study was designed to assess the neuroprotective mechanisms of edaravone, a novel free radical scavenger, through antioxidative and anti-inflammatory pathways, from the early period to up to 7 days after ischemia/reperfusion in mice. Methods - Mice were subjected to 60-minute ischemia followed by reperfusion. They were divided into the edaravone group (n = 72; with different schedules for first administration) and the vehicle (control) group (n = 36). Infarct volume and neurological deficit scores were evaluated at several time points after ischemia. Immunohistochemical analysis for 4-hydroxy-2-nonenal (HNE), 8-hydroxy-deoxyguanosine (8- OHdG), ionized calcium-binding adapter molecule 1 (Iba-1), inducible NO synthase (iNOS), and nitrotyrosine were performed at 24 hours, 72 hours, or 7 days after reperfusion. Result - Edaravone, even when administrated 6 hours after onset of ischemia/ reperfusion, significantly reduced the infarct volume (68.10 +/- 6.24%; P < 0.05) and improved the neurological deficit scores (P < 0.05) at 24 hours after reperfusion. Edaravone markedly suppressed the accumulation of HNE-modified protein and 8- OHdG at the penumbra area during the early period after reperfusion (P < 0.05) and reduced microglial activation, iNOS expression, and nitrotyrosine formation at the late period. Conclusion - Our results indicated that edaravone exerts an early neuroprotective effect through the early free radicals scavenging pathway and a late anti-inflammatory effect and suggested that edaravone is important for expansion of the therapeutic time window in stroke patients.