Transient distal platelet accumulation after common carotid artery thrombosis (CCAT) leads to structural, hemodynamic and molecular events-that may be expected to influence the response of the post-embolic brain to secondary insults. Recent experimental data indicate that a prior thromboembolic event is a risk factor for I widespread cerebral infarction and hemorrhage when combined with a dalayed ischemic insult. Proposed I studies will therefore clarify what vascular events enhance the susceptibility of the post-embolic brain to secondary injury Specific aims will determine the temporal profile of altered vulnerability using quantitative histopathological and behavioral outcome measures. Established animal models of photochemically induced thromboembolic stroke and transient cerebral ischemia will be used. Pathomechanisms including hemodynamic abnormalities, alterations in endothelial nitric oxide synthase (eNOS) mRNA and protein, and the induction of matrix-degrading metalloproteinases (MMPs) will be examined as potential mechanisms underlying the increased sensitivity. Treatment strategies including HMG CoA reductase inhibitors , L-arginine, and MMp inhibitors will be tested to counteract these vascular consequences. A recently developed model of photochemically induced thromboembolic stroke in mice will be utilized to critically compare the histopathological and behavioral consequences of CGAT in eNOS knockout mice. Because transient ischemic attacks (TIAs) have also been suggested to protect against subsequent stroke the phenomenon of ischemia tolerance after transient platelet emboleation will also be investigated. This new approach to stroke research should provide important data conceming interactions between TIAs and subsequent stroke. Neuroprotective strategies that may be given to patients with stroke risk factors to prevent the initiation of stroke will be tested.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1 (05))
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Jacobs, Tom P
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University of Miami School of Medicine
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