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

Abstract

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 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. Key Words: ischemia Ⅲ neuroprotection Ⅲ nitrogen radicals Ⅲ oxygen radicals Ⅲ reactive oxygen species Ⅲ reperfusion Ⅲ tissue plasminogen activator Ⅲ rabbits W ith the use of tissue plasminogen activator (tPA) for the treatment of thromboembolic stroke, 1-3 there is reason to be concerned that thrombolysis may expose patients to secondary intracerebral hemorrhage (ICH). 4,5 There is an approximately 6% incidence of subsequent symptomatic ICH, and half of these patients die. 4,6,7 Currently, there are no acceptable pharmacological treatments for ...

Hemorrhagic Transformation after Ischemic Stroke in Animals and Humans

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Neuroprotection for ischemic stroke: Two decades of success and failure

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The Nonpeptide Glycoprotein IIb/IIIa Platelet Receptor Antagonist SM-20302 Reduces Tissue Plasminogen Activator–Induced Intracerebral Hemorrhage After Thromboembolic Stroke

“…1 Additionally, there is substantial evidence indicating that thrombolytics increase the incidence of intracerebral hemorrhage (ICH) in preclinical animal models of stroke and, more importantly, in stroke patients. [2][3][4][5][6][7][8] With these observations in mind, there is a need to develop new drugs that may be used in combination with tPA not only to manage secondary tissue damage but also to reduce the risk of tPA-induced ICH. Because of this, we focused on specific mechanisms involved in tissue damage after an embolic stroke.…”