Further insights into the molecular mechanisms of action of the serotonergic neurotoxin 5,7-dihydroxytryptamine.
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 micrograms) and 3 (25.4 +/- 0.30 micrograms) are lower than that for 1 (51.8 +/- 0.28 micrograms). 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.-, 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.-, form the cytotoxic hydroxyl radical (HO.). 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.-. Dismutation of O2.- gives H2O2 which, as a result of transition metal ion-catalyzed Haber-Weiss chemistry, yields HO.. Thus, neuronal damage and death might result from the combined effects of hypoxia and HO. formation.
Tabatabaie
T
T
Department of Chemistry and Biochemistry, University of Oklahoma, Norman 73019-0370.
Goyal
R N
RN
Blank
C L
CL
Dryhurst
G
G
D015116:5,7-Dihydroxytryptamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D045563:Indolequinones; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009498:Neurotoxins; D018377:Neurotransmitter Agents / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000031:analogs & derivatives*
C079291:6,6'-bis(5-hydroxytryptamine-4,7-dione); D045563:Indolequinones; D009498:Neurotoxins; D018377:Neurotransmitter Agents; C079290:5-hydroxytryptamine-4,7-dione; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin