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.