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A rabbit model of cerebral microembolic signals for translational research: preclinical validation for aspirin and clopidogrel
Author(s) -
Zhou X.,
Kurowski S.,
Wu W.,
Desai K.,
Chu L.,
Gutstein D. E.,
Seiffert D.,
Wang X.
Publication year - 2016
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13377
Subject(s) - medicine , clopidogrel , aspirin , thrombus , stroke (engine) , antithrombotic , thrombosis , middle cerebral artery , cardiology , transcranial doppler , anesthesia , pharmacology , ischemia , mechanical engineering , engineering
Essentials Microembolic signal (MES) is an independent predictor of stroke risk in patients. A rabbit model of cerebral microembolic signals was established. Therapeutic efficacy was demonstrated for aspirin and clopidogrel on microembolic signals. Potential translational value of this preclinical model of MES was demonstrated.Summary Objectives Cerebral microembolic signals ( MES s) detected by transcranial Doppler ( TCD ) ultrasound constitute an independent predictor of stroke risk and prognosis. The aim of this study was to develop a novel preclinical model of MES s to facilitate translational research. Methods A clinical TCD ultrasound machine was used to detect MES s in the cerebral circulation of New Zealand White rabbits. Technical feasibility was assessed for the measurement of MES s in the middle cerebral artery ( MCA ) by TCD . FeCl 3 ‐induced carotid arterial thrombosis was optimized for the generation of endogenous microemboli. Ascending doses of two antithrombotic agents (aspirin and clopidogrel) were evaluated individually and in combination for their effects on both arterial thrombosis and MES s in a 30% FeCl 3 ‐induced carotid arterial thrombosis model, along with ex vivo functional assays. Results Dose‐dependent FeCl 3 ‐induced arterial thrombosis studies showed that 30% FeCl 3 resulted in the most consistent and reproducible MES s in the MCA (3.3 ± 0.7 MESs h −1 ). Ascending‐dose studies showed that the effective doses for 50% inhibition ( ED 50 ) of thrombus formation, based on integrated blood flow and thrombus weight, respectively, were 3.1 mg kg −1 and 4.2 mg kg −1 orally for aspirin, and 0.3 mg kg −1 and 0.28 mg kg −1 orally for clopidogrel. The ED 50 values for MES incidence were 12.7 mg kg −1 orally for aspirin, and 0.25 mg kg −1 orally for clopidogrel. Dual treatment with aspirin (5 mg kg −1 ) and clopidogel (0.3 mg kg −1 ) resulted in significant reductions in cerebral MES s ( P < 0.05) as compared with monotherapy with either agent. Conclusions Our study demonstrated the successful establishment of the MES model in rabbits, and it may provide translational value for MES s and ischemic stroke research.