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Neuroprotection afforded by antagonists of endothelin-1 receptors in experimental stroke.

Abstract
Endothelin-1 (ET-1) is involved on the development of cerebral edema in acute ischemic stroke. As edema is a therapeutic target in cerebral ischemia, our aim was to study the effect of antagonists for ET-1 receptors (Clazosentan® and BQ-788, specific antagonists for receptors A and B, respectively) on the development of edema, infarct volume and sensorial-motor deficits in rats subjected to ischemia by occlusion of the middle cerebral artery (MCAO). We used Wistar rats (280-320 g) submitted to ischemia by intraluminal transient (90 min) MCAO. After ischemia, rats were randomized into 4 groups (n = 6) treated with; 1) control group (saline), 2) Clazosentan® group (10 mg/kg iv), 3) BQ-788 group (3 mg/kg iv), and 4) combined treatment (Clazosentan® 10 mg/kg plus BQ-788 3 mg/kg iv). We observed that rats treated with Clazosentan® showed a reduction of edema, measured by MRI, at 72 h (hours) and at day 7 (both p < 0.0001), and a decrease in the serum levels of ET-1 at 72 h (p < 0.0001) and at day 7 (p = 0.009). The combined treatment also induced a reduction of edema at 24 h (p = 0.004), 72 h (p < 0.0001) and at day 7 (p < 0.0001), a reduction on infarct volume, measured by MRI, at 24 and 72 h, and at day 7 (all p < 0.01), and a better sensorimotor recovery at 24 and 72 h, and at day 7 (all p < 0.01). Moreover, Clazosentan® induced a decrease in AQP4 expression, while BQ-788 induced an increase in AQP9 expression. These results suggest that antagonists for ET-1 receptors may be a good therapeutic target for cerebral ischemia.
AuthorsOctavio Moldes, Tomás Sobrino, Miguel Blanco, Jesús Agulla, David Barral, Pedro Ramos-Cabrer, José Castillo
JournalNeuropharmacology (Neuropharmacology) Vol. 63 Issue 8 Pg. 1279-85 (Dec 2012) ISSN: 1873-7064 [Electronic] England
PMID22975409 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Aquaporins
  • Dioxanes
  • Endothelin A Receptor Antagonists
  • Endothelin B Receptor Antagonists
  • Endothelin-1
  • Neuroprotective Agents
  • Oligopeptides
  • Piperidines
  • Pyridines
  • Pyrimidines
  • Sulfonamides
  • Tetrazoles
  • clazosentan
  • BQ 788
Topics
  • Animals
  • Aquaporins (metabolism)
  • Blotting, Western
  • Brain Edema (etiology, pathology, prevention & control)
  • Brain Ischemia (complications, drug therapy)
  • Dioxanes (pharmacology)
  • Endothelin A Receptor Antagonists
  • Endothelin B Receptor Antagonists
  • Endothelin-1 (metabolism)
  • Evoked Potentials, Somatosensory (drug effects)
  • Image Processing, Computer-Assisted
  • Infarction, Middle Cerebral Artery (etiology, pathology, prevention & control)
  • Magnetic Resonance Imaging
  • Male
  • Nervous System Diseases (etiology, prevention & control)
  • Neuroprotective Agents
  • Oligopeptides (therapeutic use)
  • Piperidines (therapeutic use)
  • Pyridines (pharmacology)
  • Pyrimidines (pharmacology)
  • Rats
  • Rats, Wistar
  • Stroke (drug therapy, pathology)
  • Sulfonamides (pharmacology)
  • Tetrazoles (pharmacology)

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