Principal Investigator & Institution: Ebadi, Manuchair; Professor; Pharm/Toxicology/Therapeutics; University of North Dakota 264 Centennial Drive Grand Forks, Nd 58202
Timing: Fiscal Year 2002; Project Start 16-JUL-1999; Project End 30-JUN-2004
Summary: (Verbatim from the Applicant's Abstract) The long-term objective of the proposal is to clarify the mechanism of mitochondrial-linked apoptosis associated with aging and neurodegenerative disorders. Human mitochondrial DNA(mtDNA) deletion mutations have been found in a number of neurodegenerative diseases, including Kearns-Sayre syndrome, Leber's hereditary optic neuropathy, Alzheimer's disease, and Parkinson's disease, and with aging. Abnormalities in mitochondrial metabolism likewise have been associated with neurodegenerative disease, e.g., Huntington's disease. In addition, a decline of aerobic energy metabolism in the affected tissue is often associated with the progression of these neurodegenerative diseases. A decline in aerobic metabolism has been observed in aging tissues. Ubiquinone(coenzyme Q10), in addition to its function as an electron and proton carrier in mitochondrial electron transport coupled to ATP synthesis, acts in its reduced form(ubiqionol) as an antioxidant, inhibiting lipid peroxidation in biological membranes and protecting mitochondrial inner-membrane proteins and DNA against oxidative damage accompanying lipid peroxidation. Ubiquinol is the only known lipid-soluble antioxidant that animal cells can synthesize de novo and for which there exists enzymic mechanisms which can regenerate it from its oxidized product formed in the course of its antioxidant function. Tissue ubiqionone levels are subject to regulation by physiological factors that are related to the oxidative activity of the organism: they increase under the influence of oxidative stress, e.g. physical exercise, cold adaptation, thyroid hormone treatment, and decrease during aging. The specific aims of this proposal are: A) to ascertain the natural distribution and comprehensive pharmacokinetic parameters of ubiquinone(coenzyme Q10) and its regional distribution in the CNS; B) to search for one of the molecular links to neurodegeneration by studying the interaction among ubiquitin, ATP-dependent pathways, G actin, and neurofilaments in neurons; C) to test the effects of neuroprotectants such as selegiline on the striatal-, hippocampal-, and cortical levels of coenzyme Q10; D) to explore the antioxidant coregulation governing the status of Mn++ superoxide dismutase found in the mitochondria, Cu++, Zn++ superoxide dismutase located in the cytoplasm; and coenzyme Q10 found both in the mitochondria and cytoplasm; and E) to learn whether or not the administration of coenzyme Q10 could protect glial elements and neurons against neurotoxins such as MPTP causing Parkinsonism or NMDA- and non NMDA receptor activation causing excitatoxic disruption of Ca++ homeostasis and ensuing oxidative stress. The completion of these studies will undoubtedly provide additional items of information on reactive oxygen species-induced damage of mitochondrial DNA and the protective effects of coenzyme Q10(ubiquinol) to minimize it.
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