Endothelin B receptor agonist, IRL-1620, reduces neurological damage following permanent middle cerebral artery occlusion in rats

Endothelin and its receptors have long been considered therapeutic targets in the treatment of ischemic stroke. Recent studies indicate that ETB receptors may provide both vasodilatation and neuroprotection. The purpose of this study was to determine the effect of selectively activating the ETB receptors following permanent middle cerebral artery occlusion in rats. IRL-1620 [Suc-[Glu9,Ala11,15]-Endothelin-1(8-12)], a highly selective ETB agonist, was used alone and in conjunction with BQ788, an ETB antagonist, to determine the role of ETB 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 24 h after occlusion in animals treated with IRL-1620 (24.47 ± 4.37 mm3) versus the vehicle-treated group (153.23 ± 32.18 mm3). Blockade of ETB 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 ± 15.20 mm3, 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 ETB 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 ETB receptor levels in any of the groups. The present study demonstrates that ETB receptor activation may be a novel neuroprotective therapy in the treatment of focal ischemic stroke.

► IRL-1620 improves neurological and motor function after cerebral ischemia.
► IRL-1620 reduces infarct volume after middle cerebral artery occlusion.
► IRL-1620 reduces oxidative stress following cerebral ischemia.
► ETB receptors are a novel neuroprotective target for treating cerebral ischemia.