Analysis of combined treatment of embolic stroke in rat with r-tPA and a GPIIb/IIIa inhibitor.
Suppression of platelet activation improves the efficacy of thrombolytic therapy for stroke. Thus, combination treatment with recombinant tissue plasminogen activator (r-tPA) and 7E3 F(ab')2, a GPIIb/IIIa inhibitor that binds the platelet to fibrin, may improve the efficacy of thrombolytic therapy in embolic stroke. Magnetic resonance imaging (MRI) was used to monitor treatment response in rats subjected to embolic middle cerebral artery (MCA) occlusion (MCAo). Animals were randomized into treated (n=12) and control (n=10) groups and received intravenous combination therapy or saline, respectively, 4 hours after MCAo. Magnetic resonance imaging (MRI) measurements performed 1 hour after MCAo showed no difference between groups. However, an increased incidence (50%) of MCA recanalization was found in the treated group at 24 hours compared with 20% in the control group. The area of low cerebral blood flow at 24 and 48 hours was significantly smaller in the combination treatment group, and the lesion size, as indicated from the T2 and T1 maps, differed significantly between groups. Fluorescence microscopy measurements of cerebral microvessels perfused with fluorescein isothiocyanate-dextran and measurements of infarct volume revealed that the combination treatment significantly increased microvascular patency and reduced infarct volume, respectively, compared with the control rats. The efficacy of combination treatment 4 hours after ischemia is reflected by MRI indices of tissue perfusion, MCA recanalization, and reduction of lesion volume. The treatment also reduced secondary microvascular perfusion deficits.
Ding
Guangliang
G
Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
Jiang
Quan
Q
Zhang
Li
L
Zhang
Zheng Gang
ZG
Li
Lian
L
Knight
Robert A
RA
Ewing
James R
JR
Wang
Ying
Y
Chopp
Michael
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003911:Dextrans; D004359:Drug Therapy, Combination; D017352:Echo-Planar Imaging; D005337:Fibrin / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives*; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage*; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002542:Intracranial Embolism and Thrombosis / Q000000981:diagnostic imaging / Q000178:diet therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020768:Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000473:pathology; D010960:Plasminogen Activators / Q000008:administration & dosage*; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011859:Radiography; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage; D020521:Stroke / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*
D000911:Antibodies, Monoclonal; D003911:Dextrans; D007140:Immunoglobulin Fab Fragments; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011994:Recombinant Proteins; C015219:fluorescein isothiocyanate dextran; D005337:Fibrin; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D016650:Fluorescein-5-isothiocyanate