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

Background and Purpose-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 inform ation concerning the effectiveness of spin trap agents when administered in combination with the only Food and Drug Administration-approved pharmacolo gical agent for the treatment of stroke, the thrombolytic tissue plasminoge n activator (tPA). Thus, we determined the effects of PEN when administered before tPA on hemorrhage and infarct rate and volume. We also compared the effects of PEN with those of 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), another spin trap agent that has a different chemical structure and trappi ng profile, on the incidence of infarcts and hemorrhage. Methods-One hundred sixty-five male New Zealand White rabbits were embolize d by injecting a blood clot into the middle cerebral artery via a catheter. Five minutes after embolization, PEN or TEMPO (100 mg/kg) was infused intr avenously. Control rabbits received saline, the vehicle required to solubil ize the spin traps. In tPA studies, rabbits were given intravenous tPA star ting 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 st roke was 24%. The amount of hemorrhage was significantly increased to 77% i f the thrombolytic tPA was administered. The rabbits treated with PEN in th e absence of tPA had a 91% incidence of hemorrhage compared with 33% for th e 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 effecti ve at lysing clots (49%, 44%, and 33%, respectively) compared with the 5% r ate 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 dele terious effects when administered after an embolic stroke. However, spin tr ap agents such as PEN or TEMPO, when administered in combination with tPA, may improve the safety of tPA by reducing the incidence of tPA-induced hemo rrhage. Overall, the therapeutic benefit of spin trap agents for the treatm ent of ischemic stroke requires additional scrutiny before they can be cons idered "safe" therapeutics.