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. ? ? ?
| Gamcsik, Michael P; Clark, M Daniel; Ludeman, Susan M et al. (2011) Non-invasive monitoring of L-2-oxothiazolidine-4-carboxylate metabolism in the rat brain by in vivo 13C magnetic resonance spectroscopy. Neurochem Res 36:443-51 |
