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

缓解

• 批准号: 7660462
• 负责人: JAE HO KIM
• 金额: $ 52.02万
• 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/7660462
• 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）是所有正常组织中维持协调正常功能的最关键组织。辐射暴露后，CNS的反应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。可以说比身体上的更重要 中枢神经系统损伤的心理影响，可能导致视力丧失、瘫痪或认知功能下降。最近，我们的研究小组使用血管紧张素转换酶（ACE）抑制剂雷米普利（一种FDA批准的药物）对CNS辐射损伤的药理学缓解进行了唯一的研究。值得注意的是，即使在辐射暴露后数周给予雷米普利，也观察到功能和组织病理学评估的损伤减少。该项目基于以下假设：通过促炎介质网络抑制多细胞相互作用引起的氧化应激， 具体的药物治疗。众所周知，有三类药物可抑制氧化应激，其中两类，ACE抑制剂及其受体阻断剂和他汀类药物广泛用于人类各种心血管疾病。该项目旨在解决三类药物的特定治疗作用，ACE抑制剂和受体阻滞剂，他汀类药物和SOD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。其主要目的是证明其有效性，并优化使用药物剂量和给药时间，以减轻和治疗放射性脑损伤。评价终点为认知功能、视觉功能、血脑屏障渗透性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性变化，使用成年大鼠的单次全脑辐射。由于ACE抑制剂和他汀类药物在临床上广泛用于各种心血管疾病，因此拟议研究的阳性结果将很容易在人类中转化。总之，实验研究表明，辐射诱导的CNS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带入临床实践。