Pharmacological effects of the spin trap agents N-t-butyl-phenylnitrone (PBN) and 2,2,6, 6-tetramethylpiperidine-N-oxyl (TEMPO) in a rabbit thromboembolic stroke model: combination studies with the thrombolytic tissue plasminogen activator.
OBJECTIVE
It has been proposed that spin trap agents such as N:-t-butyl-phenylnitrone (PBN) may be useful as neuroprotective agents in the treatment of ischemia and stroke. However, to date, there is little information concerning the effectiveness of spin trap agents when administered in combination with the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of PBN when administered before tPA on hemorrhage and infarct rate and volume. We also compared the effects of PBN with those of 2,2,6, 6-tetramethylpiperidine-N:-oxyl (TEMPO), another spin trap agent that has a different chemical structure and trapping profile, on the incidence of infarcts and hemorrhage.


METHODS
One hundred sixty-five male New Zealand White rabbits were embolized by injecting a blood clot into the middle cerebral artery via a catheter. Five minutes after embolization, PBN or TEMPO (100 mg/kg) was infused intravenously. Control rabbits received saline, the vehicle required to solubilize the spin traps. In tPA studies, rabbits were given intravenous tPA starting 60 minutes after embolization. Postmortem analysis included assessment of hemorrhage, infarct size and location, and clot lysis.


RESULTS
In the control group, the hemorrhage rate after a thromboembolic stroke was 24%. The amount of hemorrhage was significantly increased to 77% if the thrombolytic tPA was administered. The rabbits treated with PBN in the absence of tPA had a 91% incidence of hemorrhage compared with 33% for the TEMPO-treated group. In the combination drug-treated groups, the PBN/tPA group had a 44% incidence of hemorrhage, and the TEMPO/tPA group had a 42% incidence of hemorrhage. tPA, PBN/tPA, and TEMPO/tPA were similarly effective at lysing clots (49%, 44%, and 33%, respectively) compared with the 5% rate of lysis in the control group. There was no significant effect of drug combinations on the rate or volume of infarcts.


CONCLUSIONS
This study suggests that certain spin trap agents may have deleterious effects when administered after an embolic stroke. However, spin trap agents such as PBN or TEMPO, when administered in combination with tPA, may improve the safety of tPA by reducing the incidence of tPA-induced hemorrhage. Overall, the therapeutic benefit of spin trap agents for the treatment of ischemic stroke requires additional scrutiny before they can be considered "safe" therapeutics.
Lapchak
P A
PA
Department of Neuroscience, University of California at San Diego, La Jolla, CA 92093-0624, USA. plapchak@ucsd.edu
Chapman
D F
DF
Zivin
J A
JA
D000818:Animals; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D003497:Cyclic N-Oxides / Q000008:administration & dosage* / Q000009:adverse effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects; D009589:Nitrogen Oxides / Q000008:administration & dosage* / Q000009:adverse effects; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D015424:Reperfusion; D013113:Spin Labels; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D013923:Thromboembolism / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; D013113:Spin Labels; C029217:phenyl-N-tert-butylnitrone; D010959:Tissue Plasminogen Activator; C003959:TEMPO