Synergy of combined tPA-edaravone therapy in experimental thrombotic stroke

Yu Yo Sun, Yury M. Morozov, Dianer Yang, Yikun Li, R. Scott Dunn, Pasko Rakic, Pak H. Chan, Koji Abe, Diana M. Lindquist, Chia Yi Kuan

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


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.

Original languageEnglish
Article numbere98807
JournalPloS one
Issue number6
Publication statusPublished - Jun 9 2014
Externally publishedYes

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Synergy of combined tPA-edaravone therapy in experimental thrombotic stroke'. Together they form a unique fingerprint.

Cite this