Paper
MECHANISM OF ACTION OF DIHYDROXYTRYPTAMINES
Published Jun 1, 1978 · C. Creveling, A. Rotman
Annals of the New York Academy of Sciences
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Abstract
Two of the autoxidizable dihydroxytryptamines, 5,6-dihydroxytryptamine (5,6-DHT) and 5,7-dihydroxytryptamine (5,7-DHT), have been shown to have a relatively selective cytotoxic action on central serotoninergic heurons.l-s In addition, 5,7-DHT has been shown to have a cytotoxic action on peripheral noradrenergic neurons.4~ The cytotoxic actions of these tryptamine derivatives are similar in many respects to the actions of autoxidizable phenethylamine derivatives, of which 6-hydroxydopamine (6-HD) is the best known e ~ a m p l e . ~ . It is now clear that the selectivity of the cytotoxic effect of 6-HD is derived from the specificity of the active uptake mechanism of 6-HD at the plasma membrane of the nerve terminal. The cytotoxic action occurs when a critical intraneuronal concentration of the amine is achieved through the action of the transport mechanism located in the plasma membrane. The subsequent events that result in the cytotoxic effect are as yet unclear. Two mechanisms have been proposed, both of which invoke the rapid autoxidation of 6-HD to form an initial oxidation product, the highly reactive paraquinone species. One reaction mechanism involves the rapid generation of toxic agents, such as hydrogen peroxide, superoxide ion, and hydroxyl radical, during the autoxidation of 6-HD; 7, the other mechanism implicates the covalent interaction of one or more of the oxidation products of the amine with intraneuronal proteins, leading to an extensive cross-linking of the proteins responsible for the cytotoxicity.slo However, the actions of both 5,6-DHT and 5,7-DHT differ in several respects from that of 6-HD. While the selectivity of the cytotoxic action of 5,7-DHT and 5,6-DHT appears to depend on an affinity for serotonin-containing neurons,3l1 such effects are not limited to serotonin-containing structures but also occur in both central and peripheral catecholamine-containing neurons. The relative selectivity results from a higher affinity of the uptake processes at serotonin-containing terminals than at catecholamine-containing terminals.lZ The specific neurotoxic action of 5,6-DHT appears to be obscured by a marked nonspecific toxicity both centrally and peripherally. 5.6-DHT induces the formation of invasive lesions of the epimyocardium without showing any effect on the noradrenergic nerve terminals of the heart.13 This finding is surprising since a variety of evidence indicates that 5,6-DHT is accumulated within noradrenergic neurons in the heart. Both 5,7-DHT and 6-HD produce neurodegenerative toxicity in noradrenergic terminals in cardiac tissue but show no tendency to cause epimyocardial lesions.1s A major difference between the properties of
Dihydroxytryptamines selectively cytotoxicize central serotoninrgic heurons and peripheral noradrenergic neurons, with their mechanism of action involving oxidative stress and covalent protein interactions.
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