5,7-Dihydroxytryptamine (5,7-DHT) is an important pharmacological tool used to produce selective chemical denervation of serotonergic neurons. The primary objectives of this program are (1) To elucidate the molecular mechanisms through which 5,7-DHT induces neurodegeneration and (2) To determine if and how 5,7-DHT and/or its ultimate product of autoxidation and a more powerful neurotoxin 5- hydroxytryptamine-4,7-dione (4,5,7-THTQ) are formed from 5- hydroxytryptamine (5-HT) under conditions mimicking certain physiological and pathophysiological states. objective 1 will be accomplished through the (i) determination of the role of metal ions in the autoxidation of 5,7-DHT; (ii) determination of peroxidase activity of the 5,7-DHT-derived hydroperoxide which is the initial product of autoxidation of 5,7-DHT; (iii) synthesis of 4- and 6-trifluoromethyl-5, 7-DHT's to probe the mechanism of mitochondria promoted oxidation of 5,7-DHT; (iv) synthesis and determination of physico-chemical properties of the products of autoxidation of 5,7-DHT-derived metabolites; (v) synthesis and determination of physico-chemical properties of rationally designed analogs of 4,5,7-THTQ (e.g., 6-trifloromethyl, 6-methyl and 5-0-methyl derivatives of 4,5,7-THTQ) and (vi) evaluation of the neurotoxicity in rat brain in vivo and the ability to undergo enzyme catalyzed redox cycling of all the compounds sharing the 5-hydroxyindole-4,7-dione nucleus (present in 4,5,7-THTQ). physico-chemical studies, when appropriate, will include determination of redox potentials, evaluation of reactivity toward glutathione and spectroscopic studies (UV, NMR, ESR). Objective 2 will be accomplished through the isolation and characterization of the products of oxidation of 5-HT by hydroxyl radical, generated in situ, and by human ceruloplasmin, a copper containing protein with oxidase activity, under both aerobic and anaerobic conditions. The results of these studies should improve our understanding of the molecular mechanism of neurodegeneration induced by 5,7-DHT and establish conditions under which 5-HT may lead to the formation of neurodegenerative products.
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