Neuroprotective Effects of the Spin Trap Agent Disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N -Oxide (Generic NXY-059) in a Rabbit Small Clot Embolic Stroke Model

Abstract

Background and Purpose — It has been proposed that the novel spin trap agent disodium-[(tert-butylimino)methyl]benzene-1,3-disulfonate N -oxide (NXY-059) may be useful in the treatment of ischemic stroke. However, there is little information concerning the neuroprotective properties of NXY-059 when administered after an embolic stroke. Moreover, there is no information available concerning the combination of NXY-059 with the only Food and Drug Administration–approved pharmacological agent for the treatment of acute stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of NXY-059G, a generic form of NXY-059, on behavioral outcome after an embolic stroke when administered alone or in combination with tPA. Methods — Male New Zealand White rabbits were embolized by injecting a suspension of small blood clots into cerebral circulation via a carotid catheter. NXY-059G (100 mg/kg) was infused intravenously 5 minutes or 3 hours after embolization, whereas control rabbits received infusions of the saline vehicle. In tPA studies, the thrombolytic was administered intravenously starting 60 minutes or 3 hours after embolization (3.3 mg/kg). In combination studies, NXY-059G was given 5 minutes after embolization, followed by the administration of tPA beginning either 60 minutes or 3 hours after embolization. Behavioral analysis was conducted 24 hours after embolization. Results — In the vehicle control group, the ES ₅₀ value (calculated as the amount of microclots [milligrams] that produce neurological dysfunction [impairment] in 50% of the rabbits within a specific treatment group) measured 24 hours after embolism was 1.04±0.31 mg, and this was increased by 153% to 2.54±0.72 mg if NXY-059G was administered beginning 5 minutes after embolization. However, if NXY-059G was administered beginning 3 hours after embolization, the ES ₅₀ was 2.01±0.40 mg. The rabbits treated with tPA alone had an ES ₅₀ of 2.64±0.66 or 0.63±0.35 mg if tPA administration started 60 minutes or 3 hours after embolization, respectively. If tPA was administered after NXY-059G (started at 5 minutes), the ES ₅₀ values were 3.15±0.50 or 2.66±0.82 if tPA administration started 60 minutes or 3 hours after embolization, respectively. Conclusions — This study suggests that NXY-059G is neuroprotective and can increase behavioral ratings if administered early after an embolic stroke. In addition, the study shows that NXY-059G can be used in combination with tPA without negative side effects. The drug combination can improve behavioral function and increase ES ₅₀ values. However, during the short time course of the behavioral analysis, the combination was not statistically better than either drug alone.