Synergistic effect of an endothelin type A receptor antagonist, S-0139, with rtPA on the neuroprotection after embolic stroke.
OBJECTIVE
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.


METHODS
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.


RESULTS
The combination therapy of S-0139 and rtPA significantly (P<0.01) reduced infarct volume (24.8+/-0.9% versus 33.8+/-1.5% in control) and hemorrhagic area (7.1+/-6.1 microm(2) versus 36.5+/-19.2 microm(2) in control) and improved functional recovery compared with control saline-treated animals. Immunostaining analysis revealed that the combination therapy had the synergistically suppressed ischemia- and rtPA-induced ICAM-1, protease-activated receptor 1 (PAR-1), as well as accumulation of platelets in cerebral microvessels. Furthermore, the combination treatment synergistically reduced loss of laminin, ZO1, and occludin in cerebral vessels.


CONCLUSIONS
These data suggest that S-0139 provides the neuroprotection by suppressing ischemia- and rtPA-triggered molecules that evoke thrombosis and BBB disruption.
Zhang
Rui Lan
RL
Department of Neurology, Henry Ford Hospital, Detroit, Michigan 48202, USA.
Zhang
Chunling
C
Zhang
Li
L
Roberts
Cindi
C
Lu
Mei
M
Kapke
Alissa
A
Cui
Yisheng
Y
Ninomiya
Mitsuyoshi
M
Nagafuji
Toshiaki
T
Albala
Bruce
B
Zhang
Zheng Gang
ZG
Chopp
Michael
M
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002109:Caffeic Acids / Q000008:administration & dosage*; D024141:Collagen Type IV / Q000096:biosynthesis / Q000187:drug effects; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051381:Rats; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000096:biosynthesis / Q000187:drug effects*; D020127:Recovery of Function / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
D002109:Caffeic Acids; D024141:Collagen Type IV; D065128:Endothelin Receptor Antagonists; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; D044463:Receptor, PAR-1; C086421:S 0139; D018799:Intercellular Adhesion Molecule-1; D009828:Oleanolic Acid; D010959:Tissue Plasminogen Activator