Dopamine- or L-DOPA-induced neurotoxicity: The role of dopamine quinone formation and tyrosinase in a model of Parkinson’s disease

Abstract

Dopamine (DA)-or L-dihydroxyphenylalanine-(L-DOPA-) induced neurotoxicity is thought to beinvolved not only in adverse reactions induced by longterm L-DOPA therapy but also in the pathogenesis of Parkinson's disease. Numerous in vitro and in vivo studies concerning DA-or L-DOPA-induced neurotoxicity have been reported in recent decades. The reactive oxygen or nitrogen species generated in the enzymatical oxidation or auto-oxidation of an excess amount of DA induce neuronal damage and/or apoptotic or non-apoptotic cell death; the DA-induced damage is prevented by various intrinsic and extrinsic antioxidants. DA and its metabolites containing two hydroxyl residues exert cytotoxicity in dopaminergic neuronal cells mainly due to the generation of highly reactive DA and DOPA quinones which are dopaminergic neuron-specific cytotoxic molecules. DA and DOPA quinones may irreversibly alter protein function through the formation of 5-cysteinyl-catechols on the proteins. For example, the formation of DA quinone-α-synuclein consequently increases cytotoxic protofibrils and the covalent modification of tyrosine hydroxylase by DA quinones. The

Proclivity to self-injurious behavior in MRL-lpr mice: implications for autoimmunity-induced damage in the dopaminergic system

“…In addition, autooxidation of dopamine produces DA-quinone, 56 a metabolite that damages proteins by reacting with cysteine residues. Since excessive levels of dopamine can be neurotoxic 57,58 one may hypothesize that accumulated dopamine metabolites contribute to loss in dopamine-neuron rich SN. Indeed, we detected earlier a significant accumulation of dopamine in the median eminence and the paraventricular nucleus, 18 as well as reduced number of TH þ cells in SN and ventral tegmentum.…”

Protective Effects of N-acetyl-L-cysteine on the Reduction of Dopamine Transporters in the Striatum of Monkeys Treated with Methamphetamine

“…As described in Introduction, the marked release of DA produced by MAP could be implicated in the neurotoxic effects on dopaminergic terminals in the brain after administration of MAP (Cadet et al, 2003;LaVoie and Hastings, 1999;Stokes et al, 1999). Two metabolic routes seem possible: (1) formation of 3,4-dihydroxyphenyl acetic acid (DOPAC) and hydrogen peroxide (H 2 O 2 ) by monoamine oxidase (MAO), or (2) formation of reactive DA-quinones and free radicals by auto-oxidation (Asanuma et al, 2003). As DA-induced modifications of protein structure and function may result in cellular toxicity, it is likely that DA quinones produced by auto-oxidation contribute to MAP-induced neurotoxicity to dopaminergic nerve terminals, supporting the evidence of oxidative stress in this model (LaVoie and Hastings, 1999;Stokes et al, 1999).…”

Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels

“…Dopamine, when left unsequestered in the pH-neutral, cytosolic compartment, is highly susceptible to oxidation into highly toxic dopamine-quinones and reactive oxygen species (ROS) (Graham et al, 1978;Asanuma et al, 2003). Cellular oxidative stress and formation of 5-cysteinyl-dopamine adducts, which irreversibly alter protein function, are only some of the severe cytotoxic consequences of dysregulated dopamine (Barzilai et al, 2001;Berman and Hastings, 1999;Blum et al, 2001).…”