Further Insights into the Molecular Mechanisms of Action of the Serotonergic Neurotoxin 5,7-Dihydroxytryptamine

Article abstract of DOI:10.1021/jm00054a006

Autoxidation and various enzyme-mediated oxidations of the serotonergic neurotoxin 5,7-dihydroxytryptamine (1) give 5-hydroxytryptamine-4,7-dione (2) and 6,6'-bi(5-hydroxytryptamine-4,7-dione) (3) as the major products.When administered into the ventricular system of mice 2 and 3 are general toxins.The LD50 values for 2 (29.6 +/- 0.04 μg) and 3 (25.4 +/- 0.30 μg) are lower than that for 1 (51.8 +/- 0.28 μg).In the presence of cellular reductants (glutathione, cysteine, ascorbate) and molecular oxygen, or when incubated with rat brain homogenate, 2 and 3 redox cycle and form superoxide radical anion, O2 radical anion, as a byproduct.The lethal effects of 2 and 3 when introduced into the brain may in part be due to such redox cycling reactions which deplete oxygen levels and, as a result of Haber-Weiss chemistry deriving from O2 radical anion, form the cytotoxic hydroxyl radical (HO-radical).Intraventricular administration of 2 and 3 to mice causes only relatively minor and transient (ca. 1 h to 1 day) changes in whole brain levels of dopamine, 5-hydroxytryptamine (from both 2 and 3), acetylcholine, and choline (from 2 only).These changes differ from the profound and long-lasting serotonergic deficit evoked by 1.On the basis of these results a hypothesis has been formulated which proposes that the selective neurotoxicity of 1 derives from its rapid uptake into serotonergic neurons where it is oxidatively converted to 2 and 3.Redox cycling reactions of 2 and 3 then result in the depletion of intraneuronal oxygen and concomitant formation of O2 radical anion.Dismutation of O2 radical anion gives H2O2 which, as a result of transition metal ion-catalyzed Haber-Weiss chemistry, yields HO-radical.Thus, neuronal damage and death might result from the combined effects of hypoxia and HO-radical formation.