Neurotoxic properties of a serotonin oxidation product: possible role in Alzheimer's disease.
Properties of a partially oxidized form of serotonin (5-HT), 4,5-diketotryptamine (4,5-DKT), synthesized by electrochemical oxidation of 5-HT, were investigated. Administration of 4,5-DKT into the lateral ventricles (i.c.v.) of rats resulted in cell death and terminal degeneration in entorhinal, insular, and posterior cingulate cortices, and in the CA1, CA3 and dentate gyrus sectors of hippocampus. Furthermore, i.c.v. administration of 4,5-DKT resulted in a significant depletion of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in prefrontal cortex, striatum and hippocampus. 4,5-DKT injection into cingulate and hippocampal cortices resulted in cell death and terminal degeneration in these structures. In brain fragment perfusion and incubation experiments, 4,5-DKT increased dose dependently 5-HT efflux from rat hippocampus and striatum. The efflux of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid from striatum was unaffected. In hippocampal preparations, fluoxetine decreased 4,5-DKT-stimulated efflux of 5-HT by 24%, and pargyline did not affect it. In vitro, 4,5-DKT bound covalently to nucleophilic -SH groups in glutathione and mercaptoethanol and the binding was blocked by N-ethyl-maleimide. 4,5-DKT bound selectively to purified guanine nucleotide binding proteins, and inhibited pertussis toxin-catalyzed ribosylation at 1nM-1 microM concentrations. Analysis of cerebrospinal fluid (CSF) by a 16-channel high pressure liquid chromatography with coulometric detection did not confirm presence of 4,5-DKT in Alzheimer CSF, but detected several peaks, significantly different in control and Alzheimer CSF, which were caused by unknown compounds.
Volicer
L
L
Department of Pharmacology, Boston University School of Medicine, MA 02118.
Chen
J C
JC
Crino
P B
PB
Vogt
B A
BA
Fishman
J
J
Rubins
J
J
Schenepper
P W
PW
Wolfe
N
N
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D045563:Indolequinones; D010084:Oxidation-Reduction; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D014363:Tryptamines / Q000378:metabolism / Q000633:toxicity*
D045563:Indolequinones; D014363:Tryptamines; C060213:tryptamine-4,5-dione; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid