Spectroscopic Imaging of Antioxidant Metabolism in the Brain

描述(申请人提供)：抗氧化剂的治疗已被提出，以减缓随着年龄增长和阿尔茨海默氏症、帕金森氏症和肌萎缩侧索硬化症等疾病发生的神经退化过程。这些抗氧化剂，如N-乙酰半胱氨酸、2-氧噻唑啉-4-羧酸酯(丙半胱氨酸)和β-谷氨酰半胱氨酸乙酯，产生用于生物合成天然抗氧化剂谷胱甘肽的底物。在大多数情况下，这些药物的治疗会提高大脑中谷胱甘肽的水平，谷胱甘肽是抵御氧化应激的主要细胞防御系统。然而，这些药物的有效性取决于是否有足够的药物输送到受氧化应激影响最大的大脑区域，以及是否存在将其加工成谷胱甘肽所需的机械设备。到目前为止，这类信息只能从组织标本的尸检分析中获得。这项提议描述了开发无创磁共振(MR)光谱成像技术的新实验，以跟踪这些抗氧化剂和谷胱甘肽在大鼠大脑中的摄取、分布和代谢。为了做到这一点，每种抗氧化剂都将被合成一个稳定的同位素标签。这一标记可以被磁共振跟踪，以监测抗氧化剂进入组织的摄取速度及其代谢成谷胱甘肽的情况。随着整个大脑代谢活动的图像的产生，将确定代谢率和谷胱甘肽水平在大脑不同区域的变化情况。由于这些方法是非侵入性的，在个体大鼠衰老或疾病进展过程中，抗氧化剂代谢的变化是可能的。此外，通过恰当地选择同位素标记的底物，可以精确地定位脑组织代谢的缺陷。这种方法的实用性将通过跟踪幼年和成熟大鼠之间抗氧化剂代谢的差异来证明。目前还没有其他可用的技术可以对大脑中的抗氧化剂新陈代谢进行非侵入性测量。由于氧化应激在衰老、疾病、中风、创伤和精神障碍中发挥作用，这项技术可能在神经科学的许多领域具有广泛的适用性。作为一项先导性研究，这项工作将在大鼠身上进行演示；然而，MR和稳定同位素方法的使用都可以转化为临床。 衰老和阿尔茨海默氏症和帕金森氏症等疾病会导致大脑功能恶化。这项提议提出了一种新的磁共振成像方法(MRI)来确定如何使用抗氧化剂来对抗这种恶化。利用大鼠衰老模型，核磁共振将被用来确定抗氧化剂治疗的有效性，并有可能减缓或逆转神经退化过程。

DESCRIPTION (provided by applicant): Treatment with antioxidants has been proposed to slow the neurodegenerative processes that occur with aging and in diseases such as Alzheimer's, Parkinsonism and amyotrophic lateral sclerosis. These antioxidants, such as N-acetylcysteine, 2-oxothiazoline-4-carboxylate (Procysteine) and ?-glutamylcysteine ethyl ester, generate substrates used in the biosynthesis of the naturally occurring antioxidant glutathione. In most cases, treatment with these agents enhances brain levels of glutathione which is the primary cellular defense against oxidative stress. The effectiveness of these agents however is dependent upon adequate delivery to the areas of the brain that are most affected by oxidative stress and the presence of the machinery needed to process them into glutathione. To date, this type of information could only be obtained from postmortem analysis of tissue specimens. This proposal delineates novel experiments to develop noninvasive magnetic resonance (MR) spectroscopic imaging techniques to follow the uptake, distribution and metabolism of these antioxidants and glutathione in rat brain. In order to do this, each antioxidant will be synthesized with a stable isotope label. This label can be tracked by MR to monitor the rate of uptake of antioxidant into tissue and its metabolism into glutathione. How metabolic rates and glutathione levels vary in different regions of the brain will be determined as images of metabolic activity across the brain will be generated. Since these methods are noninvasive, alterations in antioxidant metabolism during aging or disease progression in individual rats is possible. In addition, defects in brain tissue metabolism may be pinpointed through the proper selection of isotope-labeled substrate. The utility of this method will be demonstrated by following the differences in antioxidant metabolism between young and mature rats. There is no other technology available today that provides a noninvasive measurement of antioxidant metabolism in the brain. Since oxidative stress plays a role in aging, disease, stroke, trauma and psychiatric disorders, this technology may have broad applicability to many areas of neuroscience. As a pilot study, this work will be demonstrated in rats; however, the use of both MR and stable isotope methodology is amenable to translation into the clinic. Aging and diseases such as Alzheimer's and Parkinson's lead to deterioration in brain function. This proposal presents a new magnetic resonance imaging method (MRI) for determining how antioxidants can be used to combat this deterioration. Using a rat model of aging, MRI will be used to determine the effectiveness of antioxidant therapy with the potential to slow or reverse the neurodegenerative process.