Synergistic Effect of an Endothelin Type A Receptor Antagonist, S-0139, With rtPA on the Neuroprotection After Embolic Stroke

• Published in: Stroke (1970) 2008-10, Vol.39 (10), p.2830-2836
• Main Authors: RUI LAN ZHANG, CHUNLING ZHANG, ZHENG GANG ZHANG, CHOPP, Michael, LI ZHANG, ROBERTS, Cindi, MEI LU, KAPKE, Alissa, YISHENG CUI, NINOMIYA, Mitsuyoshi, NAGAFUJI, Toshiaki, ALBALA, Bruce
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Platelets - drug effects; Blood-Brain Barrier - drug effects; Brain - drug effects; Brain - pathology; Caffeic Acids - administration & dosage; Collagen Type IV - biosynthesis; Collagen Type IV - drug effects; Drug Synergism; Endothelin Receptor Antagonists; Fibrinolytic Agents - administration & dosage; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Immunohistochemistry; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - pathology; Intercellular Adhesion Molecule-1 - biosynthesis; Intercellular Adhesion Molecule-1 - drug effects; Male; Medical sciences; Nervous system (semeiology, syndromes); Neurology; Neuroprotective Agents - administration & dosage; Oleanolic Acid - administration & dosage; Oleanolic Acid - analogs & derivatives; Rats; Rats, Wistar; Receptor, PAR-1 - biosynthesis; Receptor, PAR-1 - drug effects; Recovery of Function - drug effects; Tight Junctions - drug effects; Tissue Plasminogen Activator - administration & dosage; Vascular diseases and vascular malformations of the nervous system
• ISSN: 0039-2499; 1524-4628
• DOI: 10.1161/STROKEAHA.108.515684

Using a model of embolic stroke, the present study tested the hypothesis that blockage of endothelin-1 with S-0139, a specific endothelin type A receptor (ET(A)) antagonist, enhances the neuroprotective effect of recombinant tissue plasminogen activator (rtPA) by suppressing molecules that mediate thrombosis and blood brain barrier (BBB) disruption induced by ischemia and rtPA. Rats (n=104) subjected to embolic middle cerebral artery (MCA) occlusion were randomly divided into 1 of 4 infusion groups with 26 rats per group: (1) the control group in which rats were administered saline, (2) the monotherapy rtPA group in which rtPA was intravenously administered at a dose of 10 mg/kg 4 hours after MCA occlusion, (3) the monotherapy S-0139 group in which S-0139 was intravenously given 2 hours after MCA occlusion, and (4) the combination of rtPA +S-0139 group in which S-0139 and rtPA were given 2 and 4 hours after MCA occlusion, respectively. Measurements of infarct volume and parenchymal hemorrhage, behavioral outcome, and immunostaining were performed on rats euthanized 1 and 7 days after stroke. The combination therapy of S-0139 and rtPA significantly (P