Spectroscopic Imaging of Antioxidant Metabolism in the Brain

描述（由申请人提供）：抗氧化剂治疗已被提议用于减缓随着衰老和阿尔茨海默氏症、帕金森病和肌萎缩侧索硬化症等疾病发生的神经退行性过程。这些抗氧化剂，如n -乙酰半胱氨酸、2-氧噻唑-4-羧酸（原半胱氨酸）和？-谷氨酰半胱氨酸乙酯，生成用于天然抗氧化剂谷胱甘肽生物合成的底物。在大多数情况下，用这些药物治疗可以提高大脑中谷胱甘肽的水平，谷胱甘肽是抵抗氧化应激的主要细胞防御。然而，这些药物的有效性取决于是否能充分输送到受氧化应激影响最大的大脑区域，以及是否存在将它们加工成谷胱甘肽所需的机制。迄今为止，这类信息只能从组织标本的死后分析中获得。本研究拟发展无创磁共振（MR）成像技术，以追踪这些抗氧化剂和谷胱甘肽在大鼠脑内的摄取、分布和代谢。为了做到这一点，每个抗氧化剂将被合成一个稳定的同位素标签。这个标签可以通过核磁共振跟踪，以监测抗氧化剂进入组织的吸收速度及其代谢为谷胱甘肽的速度。大脑不同区域的代谢率和谷胱甘肽水平如何变化，将通过生成整个大脑的代谢活动图像来确定。由于这些方法是非侵入性的，因此在个体大鼠衰老或疾病进展过程中抗氧化代谢的改变是可能的。此外，通过适当选择同位素标记的底物，可以确定脑组织代谢的缺陷。该方法的实用性将通过跟踪年轻和成熟大鼠之间抗氧化代谢的差异来证明。目前还没有其他技术可以对大脑中的抗氧化代谢进行无创测量。由于氧化应激在衰老、疾病、中风、创伤和精神疾病中起着重要作用，这项技术可能在神经科学的许多领域具有广泛的适用性。作为一项试点研究，这项工作将在大鼠身上进行验证；然而，核磁共振和稳定同位素方法的使用都可以转化为临床。

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.