Spectroscopic Imaging of Antioxidant Metabolism in the Brain

描述（由申请人提供）：已经提出用抗氧化剂治疗以减缓随着衰老和在诸如阿尔茨海默氏症、帕金森症和肌萎缩性侧索硬化症的疾病中发生的神经变性过程。这些抗氧化剂，如N-乙酰半胱氨酸、2-氧代噻唑啉-4-羧酸酯（半胱氨酸）和？谷氨酰半胱氨酸乙酯，产生用于天然存在的抗氧化剂谷胱甘肽的生物合成的底物。在大多数情况下，用这些药物治疗可提高脑中谷胱甘肽的水平，谷胱甘肽是对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递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制。迄今为止，这类信息只能从组织标本的死后分析中获得。该提案描绘了新的实验，开发非侵入性磁共振（MR）光谱成像技术，以遵循这些抗氧化剂和谷胱甘肽在大鼠大脑中的吸收，分布和代谢。为了做到这一点，每种抗氧化剂将与稳定的同位素标记合成。该标记可以通过MR跟踪以监测抗氧化剂吸收到组织中的速率及其代谢成谷胱甘肽的速率。代谢率和谷胱甘肽水平在大脑不同区域的变化将被确定为大脑代谢活动的图像。由于这些方法是非侵入性的，抗氧化剂代谢在个体大鼠衰老或疾病进展过程中的改变是可能的。此外，脑组织代谢的缺陷可以通过适当选择同位素标记的底物来确定。该方法的实用性将通过以下年轻和成熟大鼠之间的抗氧化剂代谢的差异来证明。目前还没有其他技术可以提供对大脑中抗氧化剂代谢的非侵入性测量。由于氧化应激在衰老、疾病、中风、创伤和精神疾病中起作用，因此该技术可能对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，这项工作将在大鼠中得到证明;然而，MR和稳定同位素方法的使用适合于转化为临床。 老年痴呆症和帕金森氏症等疾病会导致大脑功能恶化。该提案提出了一种新的磁共振成像方法（MRI），用于确定如何使用抗氧化剂来对抗这种恶化。使用大鼠衰老模型，MRI将用于确定抗氧化剂治疗的有效性，其具有减缓或逆转神经退行性过程的潜力。

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.