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：
8573598
负责人：
BEVERLY A RZIGALINSKI
金额：
$ 21.93万
依托单位：
VIRGINIA COLLEGE OF OSTEOPATHIC MEDICINE
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8573598
关键词：
Cerium oxide nanoparticles treatment traumatic

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.

描述（由申请人提供）：自由基被认为在创伤性脑损伤（TBI）的病理生理学中起关键作用。自由基的产生和随之而来的氧化应激状态可能有助于神经元膜的化学破坏，细胞内成分和离子通道的损害以及凋亡过程。因此，自由基活动的减少仍然是TBI的重要治疗途径，但是传统的自由基清除剂可能受到脑穿透力不良，广泛的给药要求或两者的限制。但是，纳米医学领域的新发展可能会通过传统的药理学方法提供治疗选择。该建议旨在确定氧化葡萄纳米颗粒（CEONP）是否改善功能结果并减少TBI后氧化应激。最近的研究表明，CEONP是具有出色的脑穿透力的高效自由基清除剂，并且已证明CEONP可以防止神经变性，以响应几种氧化应激的组织培养模型。此外，Ceonp的理化特性表明它们是再生自由基清除剂，与传统的抗氧化剂不同，需要有限的给药。在这些最新发现的激励下，我们认为纳米医学在TBI治疗中的应用将代表一种新型的治疗方法，该方法提供了传统药理方法无法获得的独特可能性。该提议的一个假设是TBI诱导了造成损害的自由基的产生，这些自由基压倒了先天的细胞防御，从而导致氧化应激状态。氧化应激反过来导致神经元死亡或通过几种不同的途径功能障碍，最终导致功能性不佳。因此，该提议的中心假设是，减少自由基活性和通过CEONP的给药损害具有改善TBI后功能结果的潜力。我们的初步研究表明，Ceonp在TBI的体外模型中是神经保护性的。此外，我们的初步工作表明，在大鼠实验性TBI后，CEONP的受伤前给药可改善功能结果。因此，该提案的具体目的是：1）检验以下假设：CEONP的伤害后给药通过减少自由基损害来改善TBI之后的功能结果，以及2）测试以下假设，该假说通过减少自由损害来改善TBI后CEONP的延迟后Ceonp的施用后，可改善功能性结果。这些研究的长期目标是扩大我们对自由基在TBI病理生理学中的作用的了解，提供有关氧化应激在TBI后作用中作用的信息，并提供有关纳米医学在治疗脑损伤和其他涉及氧化应激的其他疾病疾病中的潜在应用的新信息。