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 cytop lasmic superoxide (O-2(-.)) generation have both been implicated as importa nt factors associated with the degeneration of serotonergic neurons evoked by methamphetamine (MA) and cerebral ischemia-reperfusion (I-R). Such obser vations raise the possibility that tryptamine-4,5-dione (T-4,5-D), the majo r in vitro product of the O-2(-.)-mediated oxidation of 5-HT, might be an e ndotoxicant that contributes to serotonergic neurodegeneration. When incuba ted with intact rat brain mitochondria, T-4,5-D (less than or equal to 100 mu M) uncouples respiration and inhibits state 3. Experiments with rat brai n mitochondrial membrane preparations confirm that T-4,5-D evokes irreversi ble inhibition of NADH-coenzyme Q(1)(CoQ(1)) reductase and cytochrome c oxi dase (COX) apparently by covalently modifying key sulfhydryl (SH) residues at or close to the active sites of these respiratory enzyme complexes. Asco rbic acid blocks the inhibition of NADH-CoQ(1) reductase by maintaining T-4 ,5-D predominantly as 4,5-dihydroxytryptamine (4,5-DHT), thus preventing it s reaction with SH residues. In contrast, ascorbic acid potentiates the irr eversible 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 Q(2)(-.) and H2O2 that together react with trace level s of iron to form an ore-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 complexe s and contributes to the serotonergic neurodegeneration evoked by MA and I- R.