Can trace amounts of neurotoxins destroy dopamine neurons?

Hydroxyl Radical‐Mediated Oxidation of Serotonin: Potential Insights into the Neurotoxicity of Methamphetamine

“…In addition, intraneuronal formation of 5,6-DHT as a result of MA administration would also necessarily expose this substance to mitochondria, which catalyze its oxidation by molecular oxygen (Cohen and Heikkila, 1978;Singh and Dryhurst, 1990a) . Taken together, these facts might account for the sporadic and low levels of 5,6-DHT detected in rat brain following an acute dose of MA (Commins et al ., 1987), factors that have led Evans and Cohen (1989) to question the hypothesis that this neurotoxin mediates the MA-induced degeneration of serotonergic neurons . Assuming that the formation of 5,6-DHT in rat brain following MA administration reflects intraneuronal oxidation of 5-HT by HO', the present in vitro study predicts that 5-HEO, in particular, and perhaps 7/9 should also be formed as major and more stable products .…”

Potential New Insights Into the Molecular Mechanisms of Methamphetamine-Induced Neurodegeneration

“…These observations led Evans and Cohen (1989) to question the hypothesis that this neurotoxin mediates the methamphetamineinduced degeneration of serotonergic terminals. Assuming that formation of 5,6-DHT in rat brain following methamphetamine administration reflects intraneuronal oxidation of 5-HT by HO• (this is the only known chemical reaction that directly converts 5-HT and 5,6-DHT), the reaction pathways shown in figures 1 and 2 (Wrona et al 1995) predict that 5-HEO in particular (and perhaps 6 and 8) should be formed as major and more stable aberrant metabolites.…”

“…The detection of 6-OHDA (Seiden and Vosmer 1984) and 5,6-DHT (Commins et al 1987) in rat brain following methamphetamine administration has been reported to be somewhat sporadic and the concentrations measured extremely low. Indeed, several investigators have been unable to detect 6-OHDA in rat brain following methamphetamine administration (Rollema et al 1986;Evans and Cohen 1989;Karoum et al 1993). Nevertheless, a hypothesis has been advanced that under conditions of massive methamphetamineinduced release of DA and 5-HT and monoamine oxidase (MAO)-A and MAO-B inhibition (Suzuki et al 1980), these neurotransmitters are non-enzymatically oxidized in the synaptic cleft to give 6-OHDA and 5,6-DHT, respectively (Seiden et al 1988;Seiden and Vosmer 1984;Commins et al 1987).…”

“…The hypothesis that 6-OHDA and 5,6-DHT are responsible for mediating the methamphetamine-induced degeneration of dopaminergic and serotonergic terminals, respectively, has been challenged on the basis of the sporadic detection and exceedingly low levels of these neurotoxins as measured in the brain (Evans and Cohen 1989). However, in the event that these neurotoxins are formed only at, or in, axon terminals, it is not inconceivable that they might transiently reach lethal localized concen-trations.…”

Dopaminergic Neurotoxicity In Vivo and Inhibition of Mitochondrial Respiration In Vitro by Possible Endogenous Pyridinium‐Like Substances

“…A similar uncertainty pertains to the possible role of environmental pyridinium compounds as physiologically relevant neurotoxins (Michel et al, 1990). Theoretically, even a weak toxic potency could be meaningful if the effects are cumulative over a long period of time, although such cumulative effects may not be general (Evans and Cohen, 1989). There is probably a threshold governing acute MPTP intoxication; subthreshold MPTP may result in insufficient steady-state MPP+ accumulation to produce irreversible cell loss.…”