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

Abstract

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 (≤100 μM) 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.