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

Brain Res. 2011 Oct 28;1420:48-58. doi: 10.1016/j.brainres.2011.08.075. Epub 2011 Sep 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Brain Infarction / diagnosis
  • Brain Infarction / etiology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Endothelin B Receptor Antagonists
  • Endothelins / therapeutic use*
  • Gene Expression Regulation / drug effects
  • Glutathione / metabolism
  • Infarction, Middle Cerebral Artery / complications*
  • Male
  • Malondialdehyde / metabolism
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Muscle Strength / drug effects
  • Nervous System Diseases / drug therapy*
  • Nervous System Diseases / etiology*
  • Neurologic Examination
  • Oligopeptides / administration & dosage
  • Peptide Fragments / therapeutic use*
  • Piperidines / administration & dosage
  • Psychomotor Performance / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin B / agonists*
  • Receptor, Endothelin B / metabolism
  • Rotarod Performance Test / methods
  • Superoxide Dismutase / metabolism

Substances

  • Endothelin B Receptor Antagonists
  • Endothelins
  • Oligopeptides
  • Peptide Fragments
  • Piperidines
  • Receptor, Endothelin B
  • IRL 1620
  • BQ 788
  • Malondialdehyde
  • Superoxide Dismutase
  • Glutathione