Dopamine and L-dopa as selective endogenous neurotoxins

Abstract

Selective neurotoxins have the ability to exert their neurotoxic effects in some specific neuronal systems. In dopaminergic neurons, the selectivity of exogenous neurotoxins depends on their affinity to the dopamine transporter. However, dopamine and 3,4- L-dihydroxyphenylalanine (L-dopa) are synthesized in dopaminergic neurons and are likewise able to induce neurotoxicity. The possible molecular mechanisms involved in dopamine and L-dopa neurotoxicity in dopaminergic neurons are discussed. Dopamine seems to be neurotoxic in dopaminergic neurons by undergoing oxidation to aminochrome, which is the precursor to neuromelanin. However, aminochrome can be neurotoxic when it forms adducts with proteins such as alpha- synuclein, parkin, mitochondrial complexes I and III, actin, tubulin, and the dopamine transporter, or when aminochrome is one-electron reduced by flavoenzymes that use NADH, generating redox cycling with the concomitant depletion of energy and the formation of reactive oxygen species. L-dopa is also neurotoxic in cell cultures after oxidizing to a quinone species, but L-dopa seems to be a transient precursor of dopamine in that it is not able to induce neurotoxicity in vivo due to the efficient decarboxylation to dopamine catalyzed by amino acid decarboxylase. In fact, the only metabolite found in vivo is L-3-o-methyldopa, as detected in microdialysis experiments in animals treated with L-dopa. L-dopa is used in Parkinson's disease treatment, and it is still questionable whether L-dopa accelerates the degeneration of remaining dopaminergic neurons. It seems that L-dopa itself does not accelerate dopaminergic neuron degeneration because L-dopa is efficiently converted to dopamine, both in the peripheral and the central nervous systems. However, L-dopa induces dyskinesias in approximately 40 % patients with 4-6 years of treatment, and although the mechanism for L-dopa-induced dyskinesias is very complex, the rapid oscillation of striatal dopamine during L-dopa treatment has been found to be required for the induction of dyskinesias. The remaining dopaminergic neurons convert L-dopa to dopamine and release dopamine to the striatum under regulated conditions, but the majority of dopamine release to the striatum is mediated by serotonergic neurons without regulation, resulting in dyskinesias.