Abstract
Recanalization of an occluded vessel with recombinant tissue plasminogen activator is an effective strategy for treating acute ischemic stroke. Recombinant tissue plasminogen activator is administered as alteplase, a formulation containing many excipients including L-arginine, the substrate for nitric oxide production. Most studies fail to compare the effects of alteplase on brain injury to its L-arginine carrier solution. This study aimed to verify the previously reported detrimental effects of alteplase after cerebral ischemia and delineate the contribution of L-arginine. Male Wistar rats, subjected to 90 minutes of intraluminal middle cerebral artery occlusion (MCAO), were administered alteplase, the carrier solution or saline upon reperfusion. Neither alteplase nor the carrier affected cerebral blood flow (CBF) restoration throughout the first 60 minutes of reperfusion. Alteplase treatment was associated with increased mortality after MCAO. Twenty-four hours after MCAO, neurologic function and infarct volume did not differ between rats treated with alteplase, the carrier solution, or saline. Irrespective of treatment group, infarct volume was correlated with CBF during reperfusion, neuroscore, and peri-infarct depolarizations. These results suggest that alteplase treatment, independent of thrombolysis, does not cause increased ischemic injury compared with its appropriate carrier solution, supporting the continued use of alteplase in eligible ischemic stroke patients.
Highlights
Recanalization of an occluded vessel is the single most effective strategy to improve patient outcome after acute ischemic stroke.Currently, there is only one approved thrombolytic treatment for ischemic stroke, recombinant tissue plasminogen activator.Recombinant tissue plasminogen activator converts plasminogen to plasmin to break down the fibrin clot, leading to the restoration of blood flow.[1]
A large number of ischemic stroke patients benefit from recombinant tissue plasminogen activator (rtPA) through improvement of neurologic deficit and disability,[18] but rtPA produces a number of complications including intracerebral hemorrhage (ICH), secondary embolization, and angioedema.[19]
Another complication of rtPA is neurotoxicity, which has been observed in animal models of cerebral ischemia, those that use mechanical occlusion of a cerebral artery, showing that these neurotoxic effects are independent of the thrombolytic action of rtPA.[5,7]
Summary
Recombinant tissue plasminogen activator converts plasminogen to plasmin to break down the fibrin clot, leading to the restoration of blood flow.[1] Alteplase, a formulation of rtPA, has been shown to improve functional recovery in ischemic stroke patients[2] and provide benefit when administered within 4.5 hours of symptom onset.[3] After this time period, administration of alteplase can enhance the risk of hemorrhaging within the brain,[4] which limits its clinical utility to 4.5 hours post stroke. Alteplase is widely used as a first-line therapy for eligible ischemic stroke patients, but it may have neurotoxic effects.[5,6] Wang et al.[7] first showed that alteplase administration increased infarct volume in wild-type mice 24 hours after mechanical middle cerebral artery occlusion (MCAO), suggesting these neurotoxic effects were independent of its thrombolytic activity. Potential neurotoxic mechanisms proposed include the serine protease activity of rtPA, the activation of excitotoxic
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