Endothelin and its receptors have long been considered therapeutic targets in the treatment of
ischemic stroke. Recent studies indicate that ET(B) receptors may provide both vasodilatation and neuroprotection. The purpose of this study was to determine the effect of selectively activating the ET(B) receptors following permanent
middle cerebral artery occlusion in rats.
IRL-1620 [Suc-[Glu9,Ala11,15]-
Endothelin-1(8-12)], a highly selective ET(B) agonist, was used alone and in conjunction with
BQ788, an ET(B) antagonist, to determine the role of ET(B) receptors in
cerebral ischemia. Rats were assessed for neurological deficit and motor function, and their brains were evaluated to determine
infarct area, oxidative stress parameters, and ET receptor
protein levels. Animals treated with
IRL-1620 showed significant improvement in all neurological and motor function tests when compared with both vehicle-treated and BQ788-treated middle cerebral artery occluded groups. In addition, there was a significant decrease in
infarct volume 24h after occlusion in animals treated with
IRL-1620 (24.47±4.37mm(3)) versus the vehicle-treated group (153.23±32.18mm(3)). Blockade of ET(B) receptors by
BQ788 followed by either vehicle or
IRL-1620 treatment resulted in
infarct volumes similar to those of rats treated with vehicle alone (163.51±25.41 and 139.21±15.20mm(3), respectively). Lipid peroxidation, as measured by
malondialdehyde, increased and
antioxidants (
superoxide dismutase and
reduced glutathione) decreased following
infarct. Treatment with
IRL-1620 reversed these effects, indicating that ET(B) receptor activation reduces oxidative stress injury following
ischemic stroke. Animals pretreated with
BQ788 showed similar oxidative stress damage as those in the vehicle-treated group. No significant difference was observed in ET(B) receptor levels in any of the groups. The present study demonstrates that ET(B) receptor activation may be a novel neuroprotective
therapy in the treatment of focal
ischemic stroke.