Combined tissue plasminogen activator and an NK1 tachykinin receptor antagonist: an effective treatment for reperfusion injury following acute ischemic stroke in rats

Abstract

We have recently reported on the efficacy of an NK1 tachykinin receptor antagonist in improving outcome following stroke, including reduced blood-brain barrier (BBB) disruption, reduced cerebral edema and improved functional outcome. The clinically approved stroke treatment, tissue plasminogen activator (tPA), has been associated with an increased risk of hemorrhage and death, if given at later time points. Accordingly, adjunctive therapies have been investigated to reduce the adverse effects of tPA and improve outcome. The aim of the present study was to characterize the effects of a combination of an NK1 tachykinin receptor antagonist with tPA, on BBB permeability and functional outcome following transient ischemic stroke in rats. Stroke was induced in male Sprague-Dawley rats using a reversible thread model of middle cerebral artery occlusion where occlusion was maintained for 2h, followed by reperfusion. Animals received either 25mg/kg of N-acetyl-l-tryptophan or 1mg/kg of tPA, either alone or in combination, or equal volume saline vehicle, intravenously at the time of reperfusion. Functional outcome was assessed by the rotarod, bilateral asymmetry test, modified neuroscore and open field tests. BBB permeability was assessed by Evans Blue extravasation. Combination therapy of an NK1 tachykinin receptor antagonist with tPA significantly reduced BBB permeability, functional deficits and the incidence of intracerebral hemorrhage and death. As such, combined tPA-NK1 tachykinin receptor antagonist treatment may represent a novel therapeutic intervention for the treatment of reperfusion injury in acute ischemic stroke.