Kathryn J Schunke1, Thomas K Toung1, Jian Zhang1, Arvind P Pathak2, Jiadi Xu3, Jiangyang Zhang2, Raymond C Koehler1, Nauder Faraday4. 1. Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 2. The Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 3. F. M. Kirby Functional Imaging Center, Kennedy Krieger Institute, Baltimore, MD, USA. 4. Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: nfaraday@jhmi.edu.
Abstract
BACKGROUND: Most ischemic strokes in humans are caused by ruptured arterial atheroma, which activate platelets and produce thrombi that occlude cerebral vessels. METHODS: To simulate these events, we threaded a catheter through the internal carotid artery toward the middle cerebral artery (MCA) orifice and injected collagen directly into the cerebral circulation of male C57Bl/6 mice and Wistar rats. RESULTS: Laser-Doppler flowmetry demonstrated reductions in cerebral blood flow (CBF) of ∼80% in mice and ∼60% in rats. CBF spontaneously increased but remained depressed after catheter withdrawal. Magnetic resonance imaging showed that ipsilateral CBF was reduced at 3h after collagen injection and markedly improved at 48 h. Micro-computed tomography revealed reduced blood vessel density in the ipsilateral MCA territory at 3 h. Gross examination of excised brains revealed thrombi within ipsilateral cerebral arteries at 3 h, but not 24 h, after collagen injection. Immunofluorescence microscopy confirmed that platelets and fibrinogen/fibrin were major components of these thrombi at both macrovascular and microvascular levels. Cerebral infarcts comprising ∼30% of hemispheric volume and neurobehavioral deficits were observed 48 h after ischemic injury in both mice and rats. COMPARISON WITH EXISTING METHODS: Collagen injection caused brain injury that was similar in magnitude and variability to mechanical MCA occlusion or injection of a pre-formed clot; however, alterations in CBF and the mechanism of vascular occlusion were more consistent with clinical ischemic stroke. CONCLUSION: This novel rodent model of ischemic stroke has pathophysiologic characteristics consistent with clinical atherothrombotic stroke, is technically feasible, and creates reproducible brain injury.
BACKGROUND: Most ischemic strokes in humans are caused by ruptured arterial atheroma, which activate platelets and produce thrombi that occlude cerebral vessels. METHODS: To simulate these events, we threaded a catheter through the internal carotid artery toward the middle cerebral artery (MCA) orifice and injected collagen directly into the cerebral circulation of male C57Bl/6 mice and Wistar rats. RESULTS: Laser-Doppler flowmetry demonstrated reductions in cerebral blood flow (CBF) of ∼80% in mice and ∼60% in rats. CBF spontaneously increased but remained depressed after catheter withdrawal. Magnetic resonance imaging showed that ipsilateral CBF was reduced at 3h after collagen injection and markedly improved at 48 h. Micro-computed tomography revealed reduced blood vessel density in the ipsilateral MCA territory at 3 h. Gross examination of excised brains revealed thrombi within ipsilateral cerebral arteries at 3 h, but not 24 h, after collagen injection. Immunofluorescence microscopy confirmed that platelets and fibrinogen/fibrin were major components of these thrombi at both macrovascular and microvascular levels. Cerebral infarcts comprising ∼30% of hemispheric volume and neurobehavioral deficits were observed 48 h after ischemic injury in both mice and rats. COMPARISON WITH EXISTING METHODS: Collagen injection caused brain injury that was similar in magnitude and variability to mechanical MCA occlusion or injection of a pre-formed clot; however, alterations in CBF and the mechanism of vascular occlusion were more consistent with clinical ischemic stroke. CONCLUSION: This novel rodent model of ischemic stroke has pathophysiologic characteristics consistent with clinical atherothrombotic stroke, is technically feasible, and creates reproducible brain injury.
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