Cerium oxide nanoparticles for the treatment of traumatic brain injury

纳米氧化铈治疗脑外伤

基本信息

批准号：
8180515
负责人：
BEVERLY A RZIGALINSKI
金额：
$ 18.59万
依托单位：
RADFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2012-07-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8180515
关键词：
Animal Model Animals Antioxidants Apoptotic Ascorbic Acid Behavior Behavioral Brain Brain Injuries Brain region Cerium Cessation of life Chemicals Clinical Trials Communities Data Development Disease Dose Dose-Limiting Equilibrium Exploratory Behavior Free Radical Scavengers Free Radical Scavenging Free Radicals Functional disorder Glutathione Disulfide Hippocampus (Brain)Injury Ion Channel Isoprostanes Knowledge Lipid Peroxidation Measures Mediating Membrane Metric Mission Modeling Morbidity - disease rate Motor Nerve Degeneration Neurons Outcome Oxidative Stress Pathway interactions Penetration Play Pre-Clinical Model Process Production Property Rattus Research Design Role Site Testing Therapeutic Time Tissues Toxic effect Trauma Traumatic Brain Injury United States National Institutes of Health Vitamin E Water Work base catalase cerium oxide nanoparticle clinically relevant cognitive function design functional outcomes improved in vitro Model interest meetings mortality nanomedicine nanoparticle novel novel therapeutic intervention novel therapeutics prevent regenerative response single molecule success tissue culture

项目摘要

DESCRIPTION (provided by applicant): Free radicals are thought to play a key role in the pathophysiology of traumatic brain injury (TBI). The production of free radicals and the ensuing state of oxidative stress may contribute to the chemical destruction of neuronal membranes, damage to intracellular constituents and ion channels, and apoptotic processes. The reduction of free radical activity thus remains an important avenue of treatment for TBI, yet traditional free radical scavengers may be limited by poor brain penetration, extensive dosing requirements, or both. However, new developments in the field of nanomedicine may provide treatment options not possible with traditional pharmacological approaches. This proposal is designed to determine if cerium oxide nanoparticles (CeONP) improve functional outcome and reduce oxidative stress following TBI. Recent studies suggest that CeONP are highly efficient free radical scavengers with excellent brain penetration, and CeONP have been shown to prevent neurodegeneration in response to several tissue culture models of oxidative stress. Moreover, the physicochemical properties of CeONP suggest that they are regenerative free radical scavengers that, unlike traditional antioxidants, require limited dosing. Motivated by these recent findings, we reasoned that the application of nanomedicine to the treatment of TBI would represent a novel therapeutic approach that offers unique possibilities not available with traditional pharmacological approaches. One hypothesis of this proposal is that TBI induces the production of damaging free radicals that overwhelm innate cellular defenses, resulting in a state of oxidative stress. Oxidative stress in turn results in neuronal death or dysfunction via several different pathways, ultimately resulting in poor functional outcome. Thus, the central hypothesis of this proposal is that reducing free radical activity and damage with administration of CeONP has the potential to improve functional outcome following TBI. Our preliminary studies indicate that CeONP are neuroprotective in an in vitro model of TBI. Furthermore, our preliminary work indicates that pre-injury administration of CeONP improves functional outcome following experimental TBI in rats. Thus, the specific aims of this proposal are: 1) to test the hypothesis that post-injury administration of CeONP improves functional outcome following TBI by reducing free radical damage, and 2) to test the hypothesis that delayed, post-injury administration of CeONP improves functional outcome following TBI by reducing free radical damage. The long-term objectives of these studies are to expand our knowledge of the role of free radicals in the pathophysiology of TBI, provide information on the role of oxidative stress in functional outcome following TBI, and provide novel information on the potential application of nanomedicine to the treatment of brain injury and other disease conditions involving oxidative stress. PUBLIC HEALTH RELEVANCE: Traumatic brain injury is a leading cause of morbidity and mortality throughout the world, yet there is currently no accepted treatment for TBI. Thus, we believe that studies designed to investigate novel therapeutic treatments for TBI are consistent with the mission of the NIH. We expect that our findings will increase understanding of the role of free radicals in the pathophysiology of TBI and their role in poor functional outcome. Furthermore, because numerous disease states are associated with free radical production and oxidative stress, we expect that our findings will be of interest to the broad community of neuroscientists.

描述（由申请人提供）：自由基被认为在创伤性脑损伤（TBI）的病理生理学中发挥着关键作用。自由基的产生和随之而来的氧化应激状态可能导致神经元膜的化学破坏、细胞内成分和离子通道的损伤以及细胞凋亡过程。因此，减少自由基活性仍然是治疗 TBI 的重要途径，但传统的自由基清除剂可能受到大脑渗透性差、剂量要求大或两者兼而有之的限制。然而，纳米医学领域的新发展可能提供传统药理学方法无法实现的治疗选择。该提案旨在确定氧化铈纳米粒子 (CeONP) 是否可以改善功能结果并减少 TBI 后的氧化应激。最近的研究表明，CeONP 是高效的自由基清除剂，具有出色的大脑渗透性，并且 CeONP 已被证明可以预防几种氧化应激组织培养模型的神经退行性变。此外，CeONP 的理化特性表明它们是再生自由基清除剂，与传统抗氧化剂不同，需要有限的剂量。受这些最新发现的启发，我们推断纳米医学在 TBI 治疗中的应用将代表一种新颖的治疗方法，它提供了传统药理学方法所不具备的独特可能性。该提议的一个假设是，TBI 会诱导产生破坏性自由基，从而压倒先天细胞防御，导致氧化应激状态。氧化应激反过来会通过几种不同的途径导致神经元死亡或功能障碍，最终导致功能结果不佳。因此，该提案的中心假设是，通过给予 CeONP 减少自由基活性和损伤有可能改善 TBI 后的功能结果。我们的初步研究表明，CeONP 在体外 TBI 模型中具有神经保护作用。此外，我们的初步工作表明，损伤前给予 CeONP 可改善大鼠实验性 TBI 后的功能结果。因此，该提案的具体目标是：1) 检验损伤后给予 CeONP 通过减少自由基损伤改善 TBI 后功能结果的假设，以及 2) 检验延迟损伤后给予 CeONP 的假设通过减少自由基损伤来改善 TBI 后的功能结果。这些研究的长期目标是扩大我们对自由基在 TBI 病理生理学中作用的认识，提供有关氧化应激在 TBI 后功能结果中的作用的信息，并提供有关纳米医学潜在应用的新信息。治疗脑损伤和其他涉及氧化应激的疾病。公共卫生相关性：创伤性脑损伤是全世界发病和死亡的主要原因，但目前尚无公认的 TBI 治疗方法。因此，我们相信旨在研究 TBI 新型治疗方法的研究与 NIH 的使命是一致的。我们期望我们的研究结果将增进对自由基在 TBI 病理生理学中的作用及其在不良功能结果中的作用的理解。此外，由于许多疾病状态与自由基产生和氧化应激有关，我们预计我们的发现将引起广大神经科学家的兴趣。