Whole brain irradiation (WBI) leads to a progressive dementia in approximately 20-50% of brain tumor patients who are long-term survivors after treatment. At the present time, there are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies. We, and others, have proposed that the decline in cognitive function after WBI is exacerbated by increasing age and part of the mechanisms contributing to these impairments is a decrease in vascular density, and function of endothelial cells and the blood brain barrier. We hypothesize that fractionated WBI results in cognitive impairment by exacerbating age-related cerebrovascular rarefaction resulting in a decline in cerebral blood flow and impairments in glucose metabolism; these alterations (together with impairments in VEGF secretion) are a contributing factor in the decline in cognitive function and can be modulated by inhibition of the brain renin angiotensin system (RAS). The following aims are proposed: 1. Assess rarefaction of brain microvasculature and the corresponding decline in local cerebral blood flow (LCBF) after irradiation in brain regions specifically associated with learning and memory. 2. Determine whether trophic factors (e.g. VEGF and its receptors) produced by the vasculature and glia and found to be necessary for hippocampally- dependent processes of learning and memory are reduced in the hippocampal microenvironment of irradiated animals. 3. Assess whether irradiation results in microvascular endothelial dysfunction and disruptions in blood brain barrier integrity and whether the effects of irradiation are ameliorated by inhibition of the RAS system. 4. Determine whether administration of an ACE inhibitor (ramipril) or an AT1 receptor antagonist (losartan) (that have been shown to prevent radiation induced damage) ameliorate the radiation- induced decline in vascular density, LCBF, glucose metabolism and associated with improved cognitive status/The significance/innovation of this application is that the effects of a clinically relevant fractionated dose of WBI will be used, dependent variables will be assessed in animals of known cognitive status and studies will be conducted in middle-aged animals. These procedures will allow us to make more precise conclusions related to the etiology of cognitive impairment that occurs in response to WBI and assess the efficacy of interventions to reduce cognitive impairment after radiation. ? ? ?
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