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

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 13, 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 It after ischemia (p < 0.05 versus vehicle). Inhibition of B-2 receptors during ischemia, i.e. when the inhibitor was given I h after MCAo, reduced infarct volume in the basal ganglia and in the cortex by 49% (p < 0.05) and 26% (p < 0.05), resp < ectively. Inhibition of B-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 < 0.05). 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. (c) 2006 Elsevier Ltd. All rights reserved.