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


RESULTS
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.


CONCLUSIONS
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.
Zhang
Ning
N
Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo 113-0033, Japan.
Komine-Kobayashi
Miki
M
Tanaka
Ryota
R
Liu
Meizi
M
Mizuno
Yoshikuni
Y
Urabe
Takao
T
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077553:Edaravone; D004591:Electrophoresis, Polyacrylamide Gel; D016166:Free Radical Scavengers / Q000494:pharmacology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress; D015427:Reperfusion Injury / Q000188:drug therapy*; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
D000447:Aldehydes; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; C002744:3-nitrotyrosine; D014443:Tyrosine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; C027576:4-hydroxy-2-nonenal; D000077553:Edaravone; D000983:Antipyrine