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(Stroke. 2002;33:1411.)
© 2002 American Heart Association, Inc.

Original Contributions

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

Combination Studies With the Thrombolytic Tissue Plasminogen Activator

Paul A. Lapchak, PhD; Dalia M. Araujo, PhD; Donghuan Song, MD; Jiandong Wei, MD Justin A. Zivin, MD, PhD

From the Department of Neuroscience, University of California at San Diego (P.A.L., D.S., J.W., J.A.Z.); VA San Diego Healthcare System (P.A.L., D.M.A., D.S., J.W., J.A.Z.); and Veterans Medical Research Foundation (P.A.L., J.A.Z.), San Diego, Calif.

Correspondence to Dr Paul A. Lapchak, Department of Neuroscience, University of California at San Diego, MTF 316, 9500 Gilman Dr, La Jolla, CA 92093-0624. E-mail plapchak{at}ucsd.edu

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 ES₅₀ 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 ES₅₀ was 2.01±0.40 mg. The rabbits treated with tPA alone had an ES₅₀ 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 ES₅₀ 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 ES₅₀ values. However, during the short time course of the behavioral analysis, the combination was not statistically better than either drug alone.

Key Words: indoles • ischemia • neuroprotection • nitrogen oxides • oxygen radical • reactive oxygen species • reperfusion • tissue plasminogen activator • rabbits

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