The lipophilic multifunctional antioxidant edaravone (radicut) improves behavior following embolic strokes in rabbits: A combination therapy study with tissue plasminogen activator

Abstract

Edaravone is a lipophilic drug with multiple mechanisms of action. Because edaravone is a promising drug candidate for the treatment of stroke, we tested the hypothesis that edaravone would be neuroprotective following cerebral ischemia using a rabbit embolic stroke model with a well-defined behavioral endpoint. Using the rabbit small clot embolic stroke model (RSCEM), a drug or drug combination is considered beneficial if it significantly increases the amount of microclots (mg) measured in brain that produce neurologic dysfunction in 50% of a group of animals (P 50) compared to the control group. Edaravone (100 mg/kg, SC), increased the P 50 value to 1.80 ± 0.24 mg ( p < 0.05) when administered 5 min following embolization and increased P 50 values by 195% and 161% (compared to control) when administered 1 and 3 h following embolization, respectively, but was inactive when applied 6 h following embolization, compared to the cumulative control group (P 50 = 0.93 ± 0.16 mg). To simulate the design of current clinical trials, edaravone was also given following a standard tPA regimen, which by itself increased the P 50 value to 2.72 ± 0.28 mg. When tPA was infused 1 h following embolization and edaravone was given 3 h following embolization, the P 50 was 2.68 ± 0.56 mg. This study indicates that edaravone may have substantial therapeutic benefit for the treatment of AIS since it had a therapeutic widow of at least 3 h in rabbits. Edaravone can also be administered with a thrombolytic to improve behavior.