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Serotonin neurotoxins — past and present

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Abstract

Autoxidation pathways and redox reactions of dihydroxytryptamines (5,6- and 5,7-DHT) and of 6-hydroxydopamine (6-OH-DA) are illustrated, and their potential role in aminergic neurotoxicity is discussed. It is proposed that certain aspects of the cytotoxicity of 6-OH-DA and of the DHTs, namely redox cycling of their quinone- and quinoneimine-intermediates as a source of free radicals, may also apply to quinoidal reactive intermediates and to glutathionylor cysteinyl conjugates (“thioether adducts”) ofo-dihydroxylated (catechol-like) metabolites of certain substituted amphetamines (of methylenedioxymethamphetamine (MDMA) and of methylenedioxyamphetamine (MDA). Despite similarities in their primary interaction with the plasmalemmal (serotonergic transporter/dopamine transporter, SERT/DAT) and vesicular monoamine transporters (VMAT2), MDMA and fenfluramine (N-ethyl-meta-trifluoromethamphetamine, Fen) differ substantially in many aspects of their metabolism, pharmacokinetics, pharmacology, and neurotoxicology profile; the consequences of these differences for neuronal response patterns and long-term survival prospects are not yet fully understood. However, sustained hyperthermia appears to be a critical factor in these differences.

Methodological requirements for adequate detection and description of pre- and postsynaptic forms of drug-induced neurotoxicity are exemplified using recently published accounts. The inclusion of microglial markers into research strategies has widened contemporary pathogenetic concepts on methamphetamine (MA) -induced neurotoxicity as an example of inflammatory neurodegeneration, thus complementing the traditional ROS and RNS-dependent stress models. Amphetamine-type neurotoxicity studies may assist in elaborating of preventive strategies for human neurodegenerative disorders.

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  1. Campus Benjamin Franklin, Institut für Anatomie, Charite Universitätsmedizin Berlin, Königin-Luise-Str. 15, 14195, Berlin, Germany

    H. G. Baumgarten

  2. Allgemeines Krankenhaus Barmbek, Neurologische Abteilung, Rübenkamp 148, 22307, Hamburg, Germany

    L. Lachenmayer

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Baumgarten, H.G., Lachenmayer, L. Serotonin neurotoxins — past and present. neurotox res 6, 589–614 (2004). https://doi.org/10.1007/BF03033455

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