Cerium oxide nanoparticles for the treatment of traumatic brain injury

描述(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细胞膜的化学破坏，细胞内成分和离子通道的破坏，以及细胞凋亡过程。因此，降低自由基活性仍然是治疗脑损伤的重要途径，然而传统的自由基清除剂可能会受到脑组织渗透性差、广泛的剂量要求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不可能提供的治疗选择。这项建议旨在确定氧化铈纳米颗粒(CeONP)是否改善了脑外伤后的功能结局并减少了氧化应激。最近的研究表明CeONP是一种高效的自由基清除剂，具有良好的脑穿透能力，并且CeONP已被证明在几种组织培养模型的氧化应激反应中可以防止神经退行性变。此外，CeONP的物理化学性质表明，它们是再生自由基清除剂，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，我们认为，将纳米药物应用于脑外伤的治疗将代表着一种新的治疗方法，提供了传统药理学方法所不具备的独特可能性。这一建议的一个假设是，脑外伤导致破坏性自由基的产生，从而压倒固有的细胞防御，导致氧化应激状态。氧化应激通过几种不同的途径导致神经元死亡或功能障碍，最终导致不良的功能结局。因此，这一建议的中心假设是，使用CeONP减少自由基活性和损伤具有改善脑外伤后功能转归的潜力。我们的初步研究表明，CeONP在体外脑损伤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改善了大鼠实验性脑创伤后的功能结果。因此，这项建议的具体目的是：1)检验损伤后给予CeONP通过减少自由基损伤而改善脑损伤后功能结局的假设，以及2)检验延迟给予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脑损伤病理生理学中的作用的认识，提供关于氧化应激在脑损伤后功能转归中的作用的信息，并为纳米药物在脑损伤和其他涉及氧化应激的疾病的治疗中的潜在应用提供新的信息。 公共卫生相关性：创伤性脑损伤是全世界发病率和死亡率的主要原因，但目前还没有公认的治疗方法。因此，我们认为旨在研究脑外伤新疗法的研究与美国国立卫生研究院的使命是一致的。我们期望我们的发现将增加对自由基在脑外伤病理生理学中的作用以及它们在不良功能结局中的作用的理解。此外，由于许多疾病状态与自由基的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。

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.