Tryptamine-4,5-dione, a putative endotoxic metabolite of the superoxide-mediated oxidation of serotonin, is a mitochondrial toxin: possible implications in neurodegenerative brain disorders.
The release and subsequent reuptake of 5-hydroxytryptamine (5-HT) and cytoplasmic superoxide (O2-*) generation have both been implicated as important factors associated with the degeneration of serotonergic neurons evoked by methamphetamine (MA) and cerebral ischemia-reperfusion (I-R). Such observations raise the possibility that tryptamine-4,5-dione (T-4,5-D), the major in vitro product of the O2-*-mediated oxidation of 5-HT, might be an endotoxicant that contributes to serotonergic neurodegeneration. When incubated with intact rat brain mitochondria, T-4,5-D (< or = 100 microM) uncouples respiration and inhibits state 3. Experiments with rat brain mitochondrial membrane preparations confirm that T-4,5-D evokes irreversible inhibition of NADH-coenzyme Q1 (CoQ1) reductase and cytochrome c oxidase (COX) apparently by covalently modifying key sulfhydryl (SH) residues at or close to the active sites of these respiratory enzyme complexes. Ascorbic acid blocks the inhibition of NADH-CoQ1 reductase by maintaining T-4,5-D predominantly as 4, 5-dihydroxytryptamine (4,5-DHT), thus preventing its reaction with SH residues. In contrast, ascorbic acid potentiates the irreversible inhibition of COX by T-4,5-D. This may be because the T-4,5-D-4, 5-DHT couple redox cycles in the presence of excess ascorbate and molecular oxygen to cogenerate O2-* and H2O2 that together react with trace levels of iron to form an oxo-iron complex that selectively damages COX. Thus, T-4,5-D might be an endotoxicant that, dependent on intraneuronal conditions, mediates irreversible damage to mitochondrial respiratory enzyme complexes and contributes to the serotonergic neurodegeneration evoked by MA and I-R.
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D004731:Endotoxins / Q000378:metabolism*; D066298:In Vitro Techniques; D045563:Indolequinones; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D014363:Tryptamines / Q000378:metabolism* / Q000633:toxicity*