Cerium oxide nanoparticles for the treatment of traumatic brain injury

描述（由申请人提供）：自由基被认为在创伤性脑损伤（TBI）的病理生理中起关键作用。自由基的产生和随后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，降低自由基活性仍然是治疗创伤性脑损伤的重要途径，然而传统的自由基清除剂可能受到脑穿透性差、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提供的治疗选择。本研究旨在确定氧化铈纳米颗粒（CeONP）是否能改善脑外伤后的功能结局并减少氧化应激。最近的研究表明，CeONP是一种高效的自由基清除剂，具有良好的脑渗透能力，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的物理化学性质表明，它们是再生自由基清除剂，不像传统的抗氧化剂，需要有限的剂量。受这些最新发现的启发，我们推断纳米药物在TBI治疗中的应用将代表一种新的治疗方法，它提供了传统药理学方法无法提供的独特可能性。这一提议的一个假设是，脑外伤诱导了破坏性自由基的产生，这些自由基压倒了先天的细胞防御，导致氧化应激状态。氧化应激反过来通过几种不同的途径导致神经元死亡或功能障碍，最终导致功能不良。因此，本研究的中心假设是，使用CeONP降低自由基活性和损伤有可能改善脑外伤后的功能结果。我们的初步研究表明，CeONP对体外创伤性脑损伤模型具有神经保护作用。此外，我们的初步研究表明，损伤前给药CeONP可以改善大鼠实验性脑损伤后的功能结果。因此，本研究的具体目的是：1)验证损伤后给药CeONP通过减少自由基损伤改善脑损伤后功能结局的假设；2)验证延迟给药CeONP通过减少自由基损伤改善脑损伤后功能结局的假设。这些研究的长期目标是扩大我们对自由基在创伤性脑损伤病理生理中的作用的认识，提供氧化应激在创伤性脑损伤后功能结局中的作用的信息，并提供纳米药物在脑损伤和其他涉及氧化应激的疾病治疗中的潜在应用的新信息。

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.