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 1.0mg/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 6.5h (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 4.5h after ischemia (p<0.05 versus vehicle). Inhibition of B(2) receptors during ischemia, i.e. when the inhibitor was given 1h after MCAo, reduced infarct volume in the basal ganglia and in the cortex by 49% (p<0.05) and 26% (p<0.05), respectively. 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 6.5h 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.
Kläsner
Benjamin
B
Institute for Surgical Research, University of Munich Medical Center, Grosshadern, Germany.
Lumenta
David B
DB
Pruneau
Didier
D
Zausinger
Stefan
S
Plesnila
Nikolaus
N
D000818:Animals; D001835:Body Weight; D065094:Bradykinin B2 Receptor Antagonists; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2 / Q000378:metabolism
D065094:Bradykinin B2 Receptor Antagonists; D043782:Receptor, Bradykinin B2