Cytotoxic and genotoxic potential of dopamine

Abstract

A variety of in vitro and in vivo studies demonstrate that dopamine is a toxic molecule that may contribute to neurodegenerative disorders such as Parkinson's disease and ischemia-induced striatal damage. While much attention has focused on the fact that the metabolism of dopamine produces reactive oxygen species (peroxide, superoxide, and hydroxyl radical), growing evidence suggests that the neurotransmitter itself may play a direct role in the neurodegenerative process. Oxidation of the dopamine molecule produces a reactive quinone moiety that is capable of covalently modifying and damaging cellular macromolecules. This quinone formation occurs spontaneously, can be accelerated by metal ions (manganese or iron), and also arises from selected enzyme-catalyzed reactions. Macromolecular damage, combined with increased oxidant stress, may trigger cellular responses that eventually lead to cell death. Reactive quinones have long been known to represent environmental toxicants and, within the context of dopamine metabolism, may also play a role in pathological processes associated with neurodegeneration. The present discussion will review the oxidative metabolism of dopamine and describe experimental evidence suggesting that dopamine quinone may contribute to the cytotoxic and genotoxic potential of this essential neurotransmitter.

Rottlerin protected dopaminergic cell line from cytotoxicity of 6-hydroxydopamine by inhibiting PKCδ phosphorylation

“…Parkinson's disease, also termed the shaking palsy, occurs primarily in the elderly and is characterized with severe motor disturbances and lower life quality in patients [9,10] . With the aging of world population, the incidence of Parkinson's disease is obviously increasing, while its pathogenesis is still unclear.…”

RNA interference mediated silencing of α-synuclein in MN9D cells and its effects on cell viability

“…A marked increase in cytosolic DA levels may account for decreased cell viability. DA can readily oxidize to generate hydrogen peroxide, superoxide and reactive DA quinones [47,48] , which are cytotoxic due to their inhibitory effects on the mitochondrial respiratory system [49,50] . In addition, superfluous DA itself may be cytotoxic via inhibition of mitochondrial complex I activity [51] .…”

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…This mechanism may play a role in the degenerative process in PD [122]. Dopamine was found to modify proteins associated with the genetic forms of PD, such as alphaͲsyn [123], parkin [124], LRKK2 or UCHͲL1 [125].…”