A simple and reproducible cerebral thrombosis model in rats induced by a photochemical reaction and the effect of a plasminogen-plasminogen activator chimera in this model

Matsuno, Hiroyuki; Uematsu, Toshihiko; Umemura, Kazuo; Takiguchi, Yoshiharu; Asai, Yoshihiro; Muranaka, Yoshihiro; Nakashima, Mitsuyoshi

doi:10.1016/1056-8719(93)90068-p

Cited by 44 publications

(26 citation statements)

References 13 publications

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“…This permitted visualization of the intracranial dura and the right MCA could be observed without cutting FK419 on ischemic brain damage in monkey M Maeda et al the dura mater. Thrombus was induced by a photochemical reaction according to the method of Umemura et al (1993). Briefly, the window was irradiated with green light (wave length 540 nm, 2,500,000 lx) achieved by the use of a xenon lamp (L4887, Hamamatsu Photonics, Hamamatsu, Japan) with a heat-absorbing filter and a green filter.…”

Section: Photochemically Induced Thrombotic Middle Cerebral Artery Ocmentioning

confidence: 99%

FK419, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Ameliorates Brain Infarction Associated with Thrombotic Focal Cerebral Ischemia in Monkeys: Comparison with Tissue Plasminogen Activator

Maeda

Moriguchi

Mihara

et al. 2005

J Cereb Blood Flow Metab

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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 (IC 50 : 88 nmol/L), but also showed disaggregatory activity to aggregated platelet (EC 50 : 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.

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Section: Photochemically Induced Thrombotic Middle Cerebral Artery Ocmentioning

confidence: 99%

FK419, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Ameliorates Brain Infarction Associated with Thrombotic Focal Cerebral Ischemia in Monkeys: Comparison with Tissue Plasminogen Activator

Maeda

Moriguchi

Mihara

et al. 2005

J Cereb Blood Flow Metab

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“…Photothrombotic occlusion of MCA is known to activate coagulation system and platelet processes and to generate free radicals. 20,21 We demonstrated that cerebral hemorrhage associated with cerebral ischemia was exacerbated by heparin administration in WT mice. However, the exacerbation was not observed in tPA KO mice.…”

Section: Introductionmentioning

confidence: 99%

Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice

Zhao

Ikeda

Ihara

et al. 2004

Blood

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Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke continues to present a major clinical problem. Rupture of the cerebral microvasculature involves the degradation and remodeling of extracellular matrix. Here we demonstrated that the delayed administration of heparin 3 hours after photothrombotic middle cerebral artery occlusion (MCAO) caused cerebral hemorrhage in wild-type (WT) mice but not in tissue plasminogen activator (tPA)-deficient knockout (KO) mice. Heparin administration increased tPA activity and its mRNA expression at 6 and 12 hours after MCAO in the ischemic hemispheres of WT mice. The expression of tPA was enhanced in microglial cells in the ischemic border zone. We also observed an exacerbation of matrix metalloproteinase (MMP) 9 expression at the mRNA level and its conversion to an active form after heparin administration in the ischemic hemisphere in WT mice but not in tPA KO mice. The increased MMP 9 expression was localized in microglial cells and endothelial cells. These findings suggest that endogenous tPA, through the enhancement of MMP 9 expression and proteolytic activation, plays an essential role in the pathogenesis of heparin-produced cerebral hemorrhage. Targeting tPA, MMP 9, or both may provide a new approach for preventing cerebral hemorrhage associated with antithrombotic therapy for stroke in humans.

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“…However, these models are not exactly mimicking the clinical situation of cerebral ischemia. The photothrombotic occlusion model results in a platelet-and fibrin-rich thrombus in the MCA at the irradiated site [7,8] , which resembles arteriosclerotic thrombus-mediated stroke. On the other hand, clots, used in an embolic model, are composed of only fibrin, not platelets.…”

Section: Discussionmentioning

confidence: 99%

“…These include MCA ligation [3] , compression [4] , coagulation, cutting [5] or embolization [6] . We established a simple and reproducible model of MCA occlusion in rats due to thrombosis, which was induced by a photochemical reaction between green light and intravenously injected rose bengal [7] .…”

Section: Introductionmentioning

confidence: 99%

Effects of Alteplase, a Thrombolytic Agent, in a Rat Photothrombotic Middle Cerebral Artery Occlusion Model

Umemura

Higo²,

Sakata³

et al. 2007

Pathophysiol Haemos Thromb

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In this study, we examined the effects of alteplase, a recombinant tissue-type plasminogen activator (t-PA), in a simple and reproducible rat middle cerebral artery (MCA) occlusion model induced by photoillumination with 12 mg/kg of rose bengal. A clinically equivalent dose of alteplase (3 mg/kg), which was administered just after thrombotic occlusion of the MCA, significantly reopened the thrombotic MCA occlusion in 16 of 23 animals (69.6%) when compared with vehicle-treated animals (8 of 22 animals, 36.4%). In addition, alteplase significantly reduced cerebral damage and improved neurological deficits. Although it has been reported that t-PA possesses neurotoxicity, the present findings suggest that alteplase was effective in a rat acute stroke model due to reopening of thrombotic MCA occlusion. This new model is very useful for investigating the efficacy of thrombolytic agents in stroke research, providing a condition similar to the clinical setting.

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A simple and reproducible cerebral thrombosis model in rats induced by a photochemical reaction and the effect of a plasminogen-plasminogen activator chimera in this model

Cited by 44 publications

References 13 publications

FK419, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Ameliorates Brain Infarction Associated with Thrombotic Focal Cerebral Ischemia in Monkeys: Comparison with Tissue Plasminogen Activator

FK419, a Nonpeptide Platelet Glycoprotein IIb/IIIa Antagonist, Ameliorates Brain Infarction Associated with Thrombotic Focal Cerebral Ischemia in Monkeys: Comparison with Tissue Plasminogen Activator

Essential role of endogenous tissue plasminogen activator through matrix metalloproteinase 9 induction and expression on heparin-produced cerebral hemorrhage after cerebral ischemia in mice

Effects of Alteplase, a Thrombolytic Agent, in a Rat Photothrombotic Middle Cerebral Artery Occlusion Model

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