Mitigating and treating radiation-induced CNS injury

中枢神经系统（CMS）是所有正常组织中对于维持协调正常功能最关键的。辐射暴露后，中枢神经系统的反应可归因于实质和血管损伤，包括少突胶质细胞、神经祖细胞和内皮细胞。辐射诱导的靶细胞死亡和随后的继发性反应性炎症过程的动态过程被认为导致细胞损失、组织损伤和功能缺陷。可以说比身体上的影响更大 损害是中枢神经系统损伤造成的心理影响，可能导致失明、瘫痪或认知功能下降。我们小组最近使用血管紧张素转换酶 (ACE) 抑制剂雷米普利（FDA 批准的药物）进行了唯一的药物缓解中枢神经系统辐射损伤的研究证明。值得注意的是，即使在辐射暴露几周后施用雷米普利，也观察到功能和组织病理学损伤的减少。该项目基于这样的假设：通过促炎介质网络抑制多细胞相互作用产生的氧化应激，可以通过以下方式减轻辐射引起的脑损伤： 具体的药物治疗。众所周知，三类药物可以抑制氧化应激，其中两类，ACE抑制剂及其受体阻滞剂和他汀类药物广泛用于治疗人类的各种心血管疾病。该项目旨在解决三类药物（ACE 抑制剂和受体阻滞剂、他汀类药物和 SOD 模拟物）在脑损伤所有阶段（即急性、早期延迟和晚期延迟反应）中的特定治疗作用。主要目标是证明其功效并优化药物剂量的使用和给药时间，以减轻和治疗放射性脑损伤。评估的终点是认知功能、视觉功能、血脑屏障渗透性的 MRI 以及神经发生、血管和神经胶质细胞的组织病理学和增殖变化，使用成年大鼠的单剂量全脑辐射。由于 ACE 抑制剂和他汀类药物在临床上广泛用于治疗各种心血管疾病，因此拟议研究的积极结果将很容易转化为人类。总之，实验研究表明辐射引起的中枢神经系统损伤是可以治疗的。该项目的目标是将这些实验方法中的一种或多种引入临床实践。

The central nervous system (CMS) 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.