INFLUENCE OF GLUTATHIONE ON THE ELECTROCHEMICAL AND ENZYMATIC OXIDATION OF SEROTONIN

Aberrant oxidative transformations of the indolic neurotransmitter 5-h ydroxytryptamine (5-HT, serotonin) might occur in serotonergic neurons in the brains of Alzheimer's disease (AD) patients. In the event that such reactions occur in serotonergic nerve terminals or axons, they w ould do so in the presence of glutathione (GSH). In this investigation the electrochemically driven and tyrosinase + O-2-mediated oxidation of 5-HT in the presence of GSH has been studied. In the absence of GSH , 5-HT is oxidized to a C(4)-centered carbocation intermediate (9a) wh ich reacts either with 5-HT, to give 5,5'-dihydroxy-4,4'-bitryptamine (2) as the major product along with a number of other carbon-carbon an d ether-linked dimers and oligomers, or with water to give tryptamine- 4,5-dione (11). In the presence of GSH this reaction is partially dive rted as a consequence of nucleophilic addition of the tripeptide to 9a to give 4-S-glutathionyl-5-hydroxytryptamine (1). Other products form ed include isomers of the 6-S-glutathionyl conjugates of dimer 2, 7-S- glutathionyltryptamine-4,5-dione (5) and glutathionyl conjugates of an indolic trimer and of two tetramers. Compound 1 might be a useful ana lytical marker molecule for unusual oxidation reactions of 5-HT in the Alzheimer brain.