ME3277, a GPIIb/IIIa Antagonist Reduces Cerebral Infarction Without Enhancing Intracranial Hemorrhage in Photothrombotic Occlusion of Rabbit Middle Cerebral Artery

Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 07/2000; 20(6):988-97. DOI: 10.1097/00004647-200006000-00011
Source: PubMed


GPIIb/IIIa antagonists are expected to have a beneficial effect on acute cerebral infarction, however, the occurrence of intracranial hemorrhage has not been as widely investigated. A rabbit focal thrombotic occlusion model of the middle cerebral artery was established by creating a photochemical reaction between green light and Rose Bengal. Hemorrhagic transformation was common in the area of cerebral infarction. Using this model, the effect of a GPIIb/IIIa antagonist, ME3277 (low dose, (L); 0.15 mg/kg + 0.125 mg/kg x h, middle dose, (M); 0.3 mg/kg + 0.25 mg/kg x h and high dose, (H); 0.6 mg/kg + 0.5 mg/kg x h), aspirin (20 mg/kg) and sodium ozagrel (thromboxane A2 synthase inhibitor, 1 mg/kg + 2 mg/ kg x h) were evaluated. Drugs were intravenously administrated 30 minutes after the photochemical reaction for 24 hours. Aspirin inhibited the ex vivo platelet aggregation induced by arachidonic acid and collagen but not by adenosine diphosphate (ADP), while sodium ozagrel only inhibited the arachidonic acid-induced aggregation. ME3277 dose-dependently inhibited the platelet aggregation induced by all the inducers (approximately 60% in L, 80% in M, and 90% in H). At 24 hours of middle cerebral artery (MCA) occlusion, infarct volume was significantly reduced by aspirin and each dose of ME3277. These agents improved neurologic deficits, with ME3277 being more potent than aspirin. Sodium ozagrel did not alter the infarct volume nor neurologic deficits. No drug was found to worsen hemorrhage volume despite increasing bleeding time (2-3 fold) in the skin. In this model, the occluded artery was spontaneously recanalized and re-thrombosed frequently. One mechanism by which antiplatelet agents reduced infarct volume was inhibition of rethrombosis of the MCA. These results suggest that treatment with a GPIIb/IIIa antagonist is a useful intervention for acute cerebral infarction prolonging dose bleeding time to 3 times the basal value.

11 Reads
  • Source
    • "This review of that scoring system in three different types of embolic stroked non-lytic rabbit groups is necessary to provide proof of the scoring concept for each system's stroke severity and its accompanying neurological deficits. Resulting deficits were evaluated by a scale similar to the 10 point scale of Kawano et al. [8] in his photochemically induced stroke model and herein called the NAS scale. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurological outcomes and behavioral assessments are widely used in animal models of stroke, but assessments in rabbit models are not fully validated. The wryneck model of neurological assessment scores (NAS) was compared to percent infarct volume (%IV) values (infarct volume is a proven clinical indicator of stroke severity) and arterial occlusion localization in three rabbit angiographic stroke models. NAS values will correlate with percent infarct volume values. Anesthetized New Zealand White rabbits (N=131, 4-5 kg) received internal carotid artery emboli by angiographic catheter introduced into the femoral artery and occlusions were characterized. Rabbits were evaluated at 24 hours post embolism using the NAS test of 0 (normal) to 10 (death). Deficit criteria included neck twist, righting reflex, extension reflex in hind paw and forepaw, and posture. Brain sections stained with triphenyltetrazolium chloride (TTC) were analyzed for %IV. Volume of the infarct was measured and calculated as a percent of the total brain volume. The aggregate correlation for NAS values vs. %IV values was R=0.61, p<0.0001, a strong positive relationship, while correlations of the NAS components ranged from R=0.28-0.46. Occlusionsof the posterior cerebral artery vs. the middle cerebral artery alone produced significantly greater deficit scores at p<0.0001. These positive results validate the NAS system in the rabbit angiographic embolic stroke model.
    The Open Neurology Journal 10/2013; 7:38-43. DOI:10.2174/1874205X01307010038
  • Source
    • "Thus, clotting in this model is considered to be more closely relevant to atherothrombosis than thromboembolism. Glycoprotein IIb/IIIa antagonists are indeed reported to be effective when treated after ischemia, not only in a photochemical thrombosis model in rabbits but also a thromboembolic model in rats in a delayed treatment (Kawano et al, 2000; Yang et al, 2001; Shuaib et al, 2002). Finally, as the best stroke recovery model has been recommended to be performed with gyrencephalic species, efficacy would ideally be examined in the other non-human primates, such as baboon or cynomolgus monkey (STAIR, 1999). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The binding of platelet glycoprotein (GP) IIb/IIIa to fibrinogen is the final common pathway in platelet aggregation, a process known to play a key role in the pathogenesis of ischemic brain damage. We compared the effects of FK419, a novel nonpeptide GPIIb/IIIa antagonist, with recombinant tissue plasminogen activator (rt-PA) on middle cerebral artery (MCA) patency and ischemic brain damage in a thrombotic stroke model in squirrel monkeys. FK419 not only inhibited in vitro platelet aggregation (IC50: 88 nmol/L), but also showed disaggregatory activity to aggregated platelet (EC50: 286 nmol/L). FK419 dose-dependently reduced the time to first reperfusion and total occlusion time of MCA blood flow when administered immediately after the termination of photoirradiation. FK419 reduced cerebral infarction and ameliorated neurologic deficits with similar dose-dependency. Although rt-PA reduced the time to first reperfusion, total occlusion time, and cerebral infarction, it did not significantly ameliorate neurologic deficits and induced petechial intracerebral hemorrhages. These results indicate: (1) FK419 restored cerebral blood flow after thrombotic occlusion of MCA, (2) FK419 reduced ischemic brain injury by its thrombolytic actions in a non-human primate stroke model, and (3) FK419 has superior antithrombotic efficacy and is safer than rt-PA.
    Journal of Cerebral Blood Flow & Metabolism 02/2005; 25(1):108-18. DOI:10.1038/sj.jcbfm.9600013 · 5.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We investigated the efficacy of heparin on cerebral ischemic damage in a rabbit model of middle cerebral artery (MCA) photothrombosis and in the same model, cerebral hemorrhage induced by heparin as its side effect was also investigated. Using a photothrombosis model in rabbits, 38 animals were divided into four groups, heparin low-dose I and II, heparin high-dose and vehicle. In heparin low-dose I (n=10) or II (n=7), heparin was administered for 23.5 or 22 h, respectively, starting 30 or 120 min after the start of photo-irradiation to induce thrombosis. In high-dose (n=7), heparin was administered 30 min after the start of photo-irradiation for 23.5 h. In the vehicle treated group (control), 14 animals were infused continuously with saline for 23.5 h. Heparin at low and high doses prolonged Activated partial thromboplastin time (aPTT) by about 3 and 10 times compared with control group. The results show that cerebral hemorrhage was present in all animals, gross hemorrhage was observed in one animal each of the heparin low-dose I and high-dose groups, and in three animals of the heparin low-dose II group, while no gross hemorrhage was observed in control group. In heparin low-dose I, the size of cerebral infarction was significantly (P<0.01) reduced and neurological deficits were significantly (P<0.01) improved. In contrast, in heparin high-dose, the infarct size significantly increased, especially in the cortex (P<0.0001), and neurological deficits were significantly (P<0.01) worsened. In heparin low-dose II, the size of cerebral hemorrhage significantly (P<0.001) increased compared with the control group. In conclusion, using a photothrombotic model in the rabbit MCA, we have investigated the antithrombotic benefits and hemorrhagic risks associated with heparin. Of unique feature of our model is the fact that in a single animal model, we could evaluate doses of heparin which reduce cerebral infarction and doses which can promote cerebral hemorrhage. This model can be extended to determine both benefits and risks of antithrombotic agents.
    Brain Research 05/2001; 902(1):30-9. DOI:10.1016/S0006-8993(01)02285-5 · 2.84 Impact Factor
Show more

Preview (2 Sources)

11 Reads
Available from