The objective of this project is to develop magnetic resonance imaging (MRI) as a tool to non-invasively evaluate and monitor recovery in stroke patients. Our studies during the current fundingperiod indicate that certain agents can enhance functional recovery after stroke in experimentalanimals based on histological and functional assessments. A prime candidate among restorativeagents is sildenafil, a phosphodiesterase type-5 inhibitor, which has been widely used in humansto increase cyclic guanosine monophosphate (cGMP). Our data show that sildenafil significantlyimproves functional recovery in both young and aged animals after stroke. Hence, we will employsildenafil in the proposed studies. We have also generated preliminary imaging data, whichindicate that certain MRI methods may be sensitive to post-stroke tissue remodeling (vascularand neuronal) events that are thought to influence eventual outcome. The studies proposed in thecurrent application expand on this theme by combining and applying these novel imaging,histological and restorative treatment strategies to assess post-stroke vascular (Aim 1) andneuronal (Aim 2) remodeling in both young and aged animals with and without restorativetherapy. MRI will be used to identify, characterize and define tissue-remodeling events thatcontribute to improvement of late-term functional outcome after stroke. These MRI assessmentswill be compared and correlated to corresponding measures of tissue remodeling determinedfrom 3D laser scanning confocal microscopy and immunohistochemistry. Finally, Aim 3 will studythe relationship between the various MRI and histological indices of neuronal and vascularremodeling and will relate these data to functional outcome as measured by a battery ofbehavioral tests. The proposed studies are novel and innovative, moving our research away fromacute diagnostics and neuroprotective therapeutic approaches for stroke treatment and toward arelatively unexplored area of late-term restorative therapy that promotes brain tissue remodelingevents that ultimately improve functional outcome. If successful, these studies are expected togenerate ground breaking information about post-stroke brain tissue remodeling that will be usefulfor monitoring stroke recovery and may lead to optimization of treatment protocols that wouldbenefit all stroke patients.
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