Integrin alpha(IIb)beta(3) inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia.
OBJECTIVE
Platelets become activated and accumulate in brain microvessels of the ischemic microvascular bed after experimental focal cerebral ischemia. The binding of glycoprotein IIb/IIIa (integrin alpha(IIb)beta(3)) on platelets to fibrinogen is the terminal step in platelet adhesion and aggregation. This study tests the hypothesis that inhibition of platelet-fibrin(ogen) interactions may prevent microvascular occlusion after experimental middle cerebral artery occlusion (MCA:O).


METHODS
TP9201 is a novel Arg-Gly-Asp (RGD)-containing integrin alpha(IIb)beta(3) inhibitor. Microvascular patency after 3-hour MCA:O and 1-hour reperfusion within the ischemic and nonischemic basal ganglia was compared in adolescent male baboons who received high-dose TP9201 (group A: IC(80) in heparin, n=4), low-dose TP9201 (group B: IC(30) in heparin, n=4), or no treatment (group C: n=4) before MCA:O.


RESULTS
After MCA:O, microvascular patency decreased significantly in group C. However, in the ischemic zones of groups A and B compared with group C, patencies were significantly greater in the 4.0- to 7. 5-microm-diameter (capillary) and 7.5- to 30.0-microm-diameter vessels (2P<0.05). A dose-dependent increase in hemorrhagic transformation was seen in group A (3 of 4 animals) compared with group B (1 of 4 animals), and no hemorrhage was visible in group C (chi(2) analysis for trend, P<0.05).


CONCLUSIONS
Platelet activation contributes significantly to ischemic microvascular occlusion. Occlusion formation may be prevented by this RGD-integrin alpha(IIb)beta(3) inhibitor at a dose that does not produce clinically significant parenchymal hemorrhage. The effect of microvascular patency on neuron recovery can now be tested.
Abumiya
T
T
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Fitridge
R
R
Mazur
C
C
Copeland
B R
BR
Koziol
J A
JA
Tschopp
J F
JF
Pierschbacher
M D
MD
del Zoppo
G J
GJ
D000818:Animals; D001479:Basal Ganglia / Q000098:blood supply; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology; D002543:Cerebral Hemorrhage / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005340:Fibrinogen / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy*; D008297:Male; D008833:Microcirculation / Q000187:drug effects*; D009842:Oligopeptides / Q000502:physiology; D010215:Papio; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D015424:Reperfusion; D014654:Vascular Patency / Q000187:drug effects*
D009842:Oligopeptides; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C047981:arginyl-glycyl-aspartic acid; C085362:TP 9201; D005340:Fibrinogen