Mitigating & treating radiation-induced CNS injury with ACE inhibitors & statins

缓解

• 批准号: 7483655
• 负责人: JAE HO KIM
• 金额: $ 52.25万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7483655
• 关键词: Accidents; Acute; Address; Adult; Angiotensin II Receptor; Angiotensin-Converting Enzyme Inhibitors; Antioxidants; Blood - brain barrier anatomy; Blood Vessels; Brain Injuries; Cardiovascular Diseases; Cells; Cessation of life; Class; Clinic; Clinical; Cranial Irradiation; Dose; Drug usage; End Point; Endothelial Cells; Evaluation; Event; Goals; Human; Impaired cognition; Impairment; Inflammatory; Injury; Intervention; Lead; Magnetic Resonance Imaging; Mediator of activation protein; Neuraxis; Neuroglia; Neurologic; Normal tissue morphology; Oligodendroglia; Outcome; Oxidative Stress; Paralysed; Peptidyl-Dipeptidase A; Permeability; Pharmaceutical Preparations; Pharmacological Treatment; Phase; Process; Psychological Impact; Radiation; Ramipril; Rattus; Reaction; Research; Role; Stress; Superoxide Dismutase; Terrorism; Therapeutic; Time; Tissues; United States Food and Drug Administration; Vision; Week; atorvastatin; base; brain irradiation injury; central nervous system injury; cognitive function; dosage; embu-sartan; mimetics; nerve injury; neurogenesis; progenitor; programs; receptor; relating to nervous system; research study; response

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.

中枢神经系统(CNS)是维持协调正常功能的最关键的正常组织。照射后，中枢神经系统的反应归因于实质和血管的损伤，包括少突胶质细胞、神经前体细胞和内皮细胞。辐射诱导的靶细胞死亡和随后的继发性反应性炎症过程被认为是导致细胞丢失、组织损伤和功能缺陷的动态过程。可以说比物理上的影响更大 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。我们团队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)进行了唯一的药理学缓解中枢神经系统辐射损伤的研究。值得注意的是，即使在辐射暴露数周后给予雷米普利，仍可观察到功能和组织病理学评估的损伤减少。该项目基于这样一种假设，即通过促炎介质网络抑制多细胞相互作用产生的氧化应激，将通过以下方式减轻辐射引起的脑损伤 特定的药物治疗。众所周知，有三类药物可以抑制氧化应激，其中两类是血管紧张素转换酶抑制剂及其受体阻滞剂和他汀类药物，广泛用于人类的各种心血管疾病。该项目旨在解决三类药物的具体治疗作用，即ACE抑制剂和受体阻滞剂、他汀类药物和超氧化物歧化酶模拟物，在脑损伤的所有阶段，即急性、早期延迟和晚期延迟反应。主要目标是证明它们的有效性，并优化药物剂量和给药时机，以减轻和治疗放射性脑损伤。使用单次剂量的成年大鼠全脑照射，评估的终点是认知功能、视觉功能、血脑屏障通透性的磁共振成像，以及神经发生、血管和神经胶质细胞的组织病理学和增殖性变化。由于血管紧张素转换酶抑制剂和他汀类药物在临床上被广泛用于各种心血管疾病，拟议中的研究结果将很容易在人类身上翻译。综上所述，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应用于临床实践。