title: Synergy of combined tPA-edaravone therapy in experimental thrombotic stroke.
abstract: Edaravone, a potent antioxidant, may improve thrombolytic therapy because it benefits ischemic stroke patients on its own and mitigates adverse effects of tissue plasminogen activator (tPA) in preclinical models. However, whether the combined tPA-edaravone therapy is more effective in reducing infarct size than singular treatment is uncertain. Here we investigated this issue using a transient hypoxia-ischemia (tHI)-induced thrombotic stroke model, in which adult C57BL/6 mice were subjected to reversible ligation of the unilateral common carotid artery plus inhalation of 7.5% oxygen for 30 min. While unilateral occlusion of the common carotid artery suppressed cerebral blood flow transiently, the addition of hypoxia triggered reperfusion deficits, endogenous thrombosis, and attenuated tPA activity, leading up to infarction. We compared the outcomes of vehicle-controls, edaravone treatment, tPA treatment at 0.5, 1, or 4 h post-tHI, and combined tPA-edaravone therapies with mortality rate and infarct size as the primary end-points. The best treatment was further compared with vehicle-controls in behavioral, biochemical, and diffusion tensor imaging (DTI) analyses. We found that application of tPA at 0.5 or 1 h--but not at 4 h post-tHI--significantly decreased infarct size and showed synergistic (p<0.05) or additive benefits with the adjuvant edaravone treatment, respectively. The acute tPA-edaravone treatment conferred >50% reduction of mortality, ∼ 80% decline in infarct size, and strong white-matter protection. It also improved vascular reperfusion and decreased oxidative stress, inflammatory cytokines, and matrix metalloproteinase activities. In conclusion, edaravone synergizes with acute tPA treatment in experimental thrombotic stroke, suggesting that clinical application of the combined tPA-edaravone therapy merits investigation.
authors.affiliation: Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Yu-Yo
authors.initials: YY
authors.lastname: Sun
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Yury M
authors.initials: YM
authors.lastname: Morozov
authors.affiliation: Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Dianer
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Yikun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Imaging Research Center, Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Dunn
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Pasko
authors.initials: P
authors.lastname: Rakic
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
authors.affiliation: Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
authors.affiliation: Imaging Research Center, Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Lindquist
authors.affiliation: Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Kuan
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D000077553:Edaravone; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000150:complications; D020767:Intracranial Thrombosis / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020521:Stroke / Q000150:complications* / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D066127:White Matter / Q000187:drug effects / Q000293:injuries
chemical_list: D010959:Tissue Plasminogen Activator; D000077553:Edaravone; D000983:Antipyrine