Acute management of ischemic stroke remains an important health problem. Thrombolytic therapy is effective but severely limited by the recommended 3-hour intravenous delivery window. It is therefore important to identify therapeutic strategies to delay the process of ischemic damage, and to extend the time window for either therapeutic or spontaneous reperfusion. An emerging target for such strategies is the leptomeningeal vasculature, which provides collateral flow during focal ischemia, such as middle cerebral artery occlusion (MCAO). Collateral enhancement beyond autoregulation could potentially raise residual perfusion above ischemic levels and retard infarct progression. However, little is known regarding the hemodynamics, vasomotor reactivity, and dilator reserve of collateral vessels during focal stroke. The overall objective of this proposal is to: (1) develop a reliable experimental model for the evaluation of leptomeningeal vasoreactivity and hemodynamics during focal ischemia, (2) determine whether hypertension, age and gender, important stroke risk factors, are associated with impaired collateral flow and vascular reactivity, and (3) develop potential pharmacological agents that specifically and safely enhance collateral flow, salvage ischemic tissue, and extend the time window for recanalization and other treatments. We will initially focus on adenosine and adenosine kinase inhibitors, which are clinically-relevant, site and event -specific vasodilator agents that may enhance collateral flow and improve outcome after ischemia. The experimental design involves a remote filament MCAO technique, cranial window methodology to monitor changes in diameter of pial arterioles, laser speckle contrast imaging, and continuous laser-Doppler perfusion measurement.
Specific Aim 1 : To evaluate collateral hemodynamics and pial arteriole dilator capacity during MCAO.
Specific Aim 2 : To determine whether site-specific dilation of pial arterioles may attenuate infarction, tissue swelling, and neurologic deficits caused by MCAO and reperfusion. In both Aims, collateral hemodynamics and effects of vasodilator agents will be evaluated in 6 groups of rats: hypertensive, normotensive, young male, young female, aged male and aged female. The studies outlined in this exploratory proposal will lead to a better understanding of collateral hemodynamics and vasoreactivity in ischemic stroke, and provide a basis for future studies aimed at developing novel collateral enhancing agents for the timely management of ischemic stroke patients.

Public Health Relevance

Ischemic stroke is a major cause of morbidity and mortality. Infarction development is critically dependent on residual perfusion, which is in turn dependent on collateral flow. This proposal focuses on collateral flow enhancement by pharmacologic dilation of leptomeningeal collaterals, as a strategy to reduce infarct expansion and to extend the time window for reperfusion and other neuroprotective therapies. The data collected may help pave the way for future studies on acute collateral pharmacotherapy in ischemic stroke.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Jacobs, Tom P
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University of Washington
Schools of Medicine
United States
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