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.
OBJECTIVE
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.
Lapchak
Paul A
PA
Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093-0624, USA. plapchak@ucsd.edu
Araujo
Dalia M
DM
Song
Donghuan
D
Wei
Jiandong
J
Zivin
Justin A
JA
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001557:Benzenesulfonates; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D020766:Intracranial Embolism / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008863:Microspheres; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D011817:Rabbits; D019097:Spin Trapping; D020521:Stroke / Q000150:complications / Q000188:drug therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D016896:Treatment Outcome
D001557:Benzenesulfonates; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; C120851:disufenton sodium; D010959:Tissue Plasminogen Activator