EFFECT OF CHRONIC HYPOXIA ON BRAIN OXYGENATION

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, mainly affecting the motor neurons. There are two forms of the disease recognized to date, spontaneous (90% of cases) and familial (10% of cases). In the familial form of ALS (FALS), there exists mutations in the superoxide dismutase (SOD) gene in approximately 40% of the patients. Several hypotheses explaining the significance of these mutations have been published; however, only two hypotheses will be pursued in this research. First, it is thought that the mutation in SOD produces a gain-of-function, perhaps being able to catalyse the nitration of tyrosine by peroxynitrite. Second, it has been found that the copper present in mutant SOD is more labile than that in wild-type, and that free copper may contribute to the disease state. The portion of this project to be conducted at Dartmouth will involve the assay of nitric oxide in mice with L-band and X-band EPR spectroscopy. The eventual goal is to compare the amount of metals and nitric oxide in Balb-C control versus transgenic mice, having copies of the G93A mutant SOD gene. To date, the selective neurotoxin 3-nitropropionic acid, an irreversible inhibitor of succinic dehydrogenase, has been used to stimulate NO production in the brain. Significant signals have been observed throughout all regions of the brain when NO is trapped by iron(II) sulfate and diethyl dithiocarbamate. This is believed to be the first observed EPR signal of endogenously synthesized NO in an intact mouse.