title: Integrin alpha(IIb)beta(3) inhibitor preserves microvascular patency in experimental acute focal cerebral ischemia.
abstract: 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.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: T
authors.initials: T
authors.lastname: Abumiya
authors.forename: R
authors.initials: R
authors.lastname: Fitridge
authors.forename: C
authors.initials: C
authors.lastname: Mazur
authors.forename: B R
authors.initials: BR
authors.lastname: Copeland
authors.forename: J A
authors.initials: JA
authors.lastname: Koziol
authors.forename: J F
authors.initials: JF
authors.lastname: Tschopp
authors.forename: M D
authors.initials: MD
authors.lastname: Pierschbacher
authors.forename: G J
authors.initials: GJ
authors.lastname: del Zoppo
mesh_terms: 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*
chemical_list: 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