Therapeutic window of bradykinin B2 receptor inhibition after focal cerebral ischemia in rats

Abstract Following cerebral ischemia bradykinin/kinin B 2 receptors mediate inflammatory responses resulting in edema formation and secondary brain damage. However, the therapeutic window for B 2 receptor inhibition determining its potential clinical use has not been investigated so far. The aim of the current study was therefore to investigate the effect of delayed B 2 receptor inhibition on morphological and functional outcome following experimental stroke. Rats were subjected to 90 min of middle cerebral artery occlusion (MCAo) by an intraluminal filament. Animals received 0.9% NaCl or 1.0 mg/kg/day Anatibant (LF 16-0687 Ms), a selective bradykinin B 2 receptor antagonist, for 3 days beginning at different time points after MCAo: 1, 2.5, 4.5, or 6.5 h ( n  = 10 per group). Neurological recovery was examined daily, infarct volume on day 7 after MCAo. Animal physiology was not influenced by B 2 receptor inhibition. Significant improvement of functional outcome was observed when treatment was delayed up to 4.5 h after ischemia ( p 2 receptors during ischemia, i.e. when the inhibitor was given 1 h after MCAo, reduced infarct volume in the basal ganglia and in the cortex by 49% ( p p 2 receptors at later time points (2.5, 4.5, or 6.5 after MCAo) reduced penumbral damage, i.e. cortical infarction, by 19–26% ( p In conclusion, the current study shows that the therapeutic window of B 2 receptor inhibition extends for up to 6.5 h after MCAo. Our data therefore suggest that inhibition of kinin B 2 receptors represents a treatment strategy for ischemic stroke which may warrant clinical validation.