The central nervous system (CNS) is the most critical of all normal tissues for maintaining coordinated normal function. Following radiation exposure, the response of the CNS has been attributable to parenchymal and vascular damages including oligodendrocytes, neural progenitors, and endothelial cells. A dynamic process of radiation-induced death of target cells and subsequent secondary reactive inflammatory process is believed to lead to cell loss, tissue damage and functional deficits. Arguably of greater consequence than the physical? damage is the psychological impact of CNS injury which could result in the loss of sight, paralysis or reduced cognitive function. The only investigational demonstration of pharmacological mitigation of CNS radiation damage was recently made by our group using the Angiotensin Converting Enzyme (ACE) inhibitor, ramipril (an FDA-approved drug). Of note, a reduction of injury assessed functionally and histopathologically was observed even when ramipril was administered weeks after the radiation exposure. This project is based on the hypothesis that the suppression of oxidative stress resulting from multi-cellular interactions through a network of pro-inflammatory mediators would mitigate radiation-induced brain injury by? specific pharmacological treatment. Three classes of drugs are well known to suppress oxidative stress and two of them, ACE inhibitors and their receptor blockers and statins are widely used in various cardiovascular disorders in humans. The project aims to address specific therapeutic roles of three classes of drugs, ACE inhibitors and receptor blockers, statins, and SOD mimetics, in all phases of the brain injury, i.e., acute, early delayed, and late delayed reactions. The primary goal is to demonstrate their efficacy and to optimize the use of drug dosage and timing of the administration to mitigate and treat the radiation brain injury. End points for evaluation are cognitive functions, visual function, MRI for permeability of the blood brain barrier, and histopathological and proliferative changes for neurogenesis, vascular and glial cells, using single doses of whole brain radiation of the adult rats. The positive findings from the proposed study will be readily translatable in humans, since both ACE inhibitors and statins are widely used in a variety of cardiovascular disorders in the clinics. In summary, experimental studies suggest radiation-induced CNS injury can be treated. The goal of this project is to bring one or more of these experimental approaches into clinical practice.?
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