Neurotoxicity of free-radical-mediated serotonin neurotoxin in cultured embryonic chick brain neurons.
Exposure of serotonin (5-HT) to oxygen-derived free-radical-generating system, xanthine oxidase-hypoxanthine or to a Fenton reaction results in the formation of the neurotoxin, tryptamine-4,5-dione. In cultured embryonic chick brain neurons, incubation of tryptamine-4,5-dione or its ethyl carbonate derivative resulted in a dose-dependent neurotoxicity (1-100 microM). The addition of sulfhydryl compound, glutathione at 2 or 10 microM significantly enhanced the toxicity induced by 10 microM tryptamine-4,5-dione. On the contrary, glutathione at 10 microM decreased the neurotoxic effect caused by 10 microM 5,6- and 5,7-dihydroxytryptamine in the cultured neurons. The toxicity resulted from 5,6- and 5,7-dihydroxytryptamine could be fully prevented by a 5-HT uptake inhibitor, fluoxetine. However, the toxicity caused by tryptamine-4,5-dione and glutathione conjugate could not be blocked by fluoxetine (10 or 100 microM) or by a glutathione transferase inhibitor, boric acid/serine. The results indicate a different molecular mechanism among 5-HT derived neurotoxins and suggest that tryptamine-4,5-dione and/or its glutathione conjugate would cause neuronal damage, if they are formed in vivo.
Chen
J C
JC
Chang-Gung College of Medicine and Technology, Department of Pharmacology, Tao-Yuan, Taiwan.
Fine
R E
RE
Squicciarini
J
J
Volicer
L
L
D015115:5,6-Dihydroxytryptamine / Q000633:toxicity; D015116:5,7-Dihydroxytryptamine / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects*; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D045563:Indolequinones; D009474:Neurons / Q000187:drug effects*; D013997:Time Factors; D014363:Tryptamines / Q000138:chemical synthesis / Q000633:toxicity*
D045563:Indolequinones; D014363:Tryptamines; C060213:tryptamine-4,5-dione; D015116:5,7-Dihydroxytryptamine; D015115:5,6-Dihydroxytryptamine