title: 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.
authors.affiliation: Clinical Neurosciences Research Laboratory, Neurovascular Area, Department of Neurology, Hospital Clínico Universitario, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Octavio
authors.initials: O
authors.lastname: Moldes
authors.forename: Tomás
authors.initials: T
authors.lastname: Sobrino
authors.forename: Miguel
authors.initials: M
authors.lastname: Blanco
authors.forename: Jesús
authors.initials: J
authors.lastname: Agulla
authors.forename: David
authors.initials: D
authors.lastname: Barral
authors.forename: Pedro
authors.initials: P
authors.lastname: Ramos-Cabrer
authors.forename: José
authors.initials: J
authors.lastname: Castillo
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000378:metabolism; D015153:Blotting, Western; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy; D004146:Dioxanes / Q000494:pharmacology; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D008279:Magnetic Resonance Imaging; D008297:Male; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control; D018696:Neuroprotective Agents; D009842:Oligopeptides / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D020346:Aquaporins; D004146:Dioxanes; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010880:Piperidines; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan; C086539:BQ 788