Ischemic stroke is a third cause of death in the US with the only FDA-approved therapy, thrombolysis by tissue plasminogen activator (tPA). Due to the high risk of fatal hemorrhages, tPA is not advised later than 3 hrs after stroke onset resultin in only 5% of patients being treated. Thus, there is a need for new interventions for the remaining 95% of patients. We propose a novel approach for stroke treatment applicable at both, early and later time after stroke onset using modulation of the hemodynamic by blood soluble drag reducing polymers (DRPs) which enhance collateral flow. Nanomolar concentrations of intravenous DRPs reduce pressure loss in arteries and arterioles by diminishing flow separations at vessel branch points and, thus, increasing precapillary pressure, which in turn increases the density of functioning capillaries. DRPs are shown to improve hemodynamics and survival in animal models of ischemic myocardium and limb but have not been tested in the brain circulation. Recently, we demonstrated that DRPs increased near-vessel-wall flow velocity in arterioles, restored perfusion in collapsed capillaries, enhanced collateral flow and reduced tissue hypoxia in the ischemic and traumatized rat brain. Since DRPs have systemic physical effects on blood circulation we formulated our central hypothesis: DRPs, through their general action on cerebrovascular circulation, can present a unique and effective therapy for stroke, applicable at both, early and later time, when tPA treatment is prohibited. The objective of this particular application is to test whether DRPs (high MW polyethylene oxide), applied within or beyond the tPA treatment window, can restore cerebral perfusion through collateral flow, reduce hypoxia, facilitate long-term protection from ischemia-induced brain damage and improve functional recovery in a rat model of permanent middle cerebral artery occlusion (pMCAO). The rationale is that demonstration of the efficacy of DRPs in the stroke treatment will provide the basis for the development of a powerful approach that can be used even beyond the tPA treatment window. The ultimate long-term goal is to develop a novel approach for the stroke treatment. To achieve this goal, a rat model of pMCAO with the application of DRPs at 0.5, 3 and 6 hours after stroke onset will be utilized. We will use various optical imaging techniques for in-vivo evaluation of the acute effects of DRPs on cerebral circulation and tissue hypoxia (SA #1), and magnetic resonance imaging, histochemistry and behavioral studies for evaluation of prolonged attenuation of ischemic injury and improving neurological outcome (SA #2).
Each aim will independently provide important new information to the field, and then taken together, these mechanistic studies will provide the basis for a novel general approach for the treatment of stroke. The development and use of this approach based on modulation of hemodynamics is innovative and the proposed research is significant since it will provide the proof of the treatment of the ischemic stroke by DRPs, applicable even to the untreatable stage by currently available methods in late or even recovery phases of the ischemic stroke.
Currently, the only approved treatment for ischemic stroke is a clot thrombolysis with tissue-type plasminogen activator (tPA) which is used in only 5% of stroke patients due to elevated risk of cerebral bleeding when given outside of the limited 3 hour delivery window for this treatment. We propose a new, independent from clot removal, approach for the treatment of ischemic stroke using modulation of the fluid properties of blood by minute concentrations of soluble drag reducing molecules targeting collateral flow enhancement, which could be applied even beyond the tPA treatment window providing care for the remaining 95% of patients and, therefore, highly relevant to public health. The project is relevant to the part o NIND's mission that pertains to advancement of our fundamental knowledge about the translation of blood flow properties modulation and resulting collateral flow enhancement into improved ischemic stroke outcomes, and the application of that knowledge in practice to reduce stroke-related disability and mortality.
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