Formation of Dopamine Adducts Derived from Brain Polyunsaturated Fatty Acids

Abstract

Oxidative stress appears to be directly involved in the pathogenesis of the neurodegeneration of dopaminergic systems in Parkinson disease. In this study, we formed four dopamine modification adducts derived from docosahexaenoic acid (C22:6/ -3) and arachidonic acid (C18:4/-6), which are known as the major polyunsaturated fatty acids in the brain. Upon incubation of dopamine with fatty acid hydroperoxides and an in vivo experiment using rat brain tissue, all four dopamine adducts were detected. Furthermore, hexanoyl dopamine (HED), an arachidonic acid-derived adduct, caused severe cytotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells, whereas the other adducts were only slightly affected. The HED-induced cell death was found to include apoptosis, which also seems to be mediated by reactive oxygen species generation and mitochondrial abnormality. Additionally, the experiments using monoamine transporter inhibitor and mouse embryonic fibroblast NIH-3T3 cells that lack the monoamine transporter indicate that the HED-induced cytotoxicity might specially occur in the neuronal cells. These data suggest that the formation of the docosahexaenoic acid-and arachidonic acid-derived dopamine adducts in vitro and in vivo, and HED, the arachidonic acid-derived dopamine modification adduct, which caused selective cytotoxicity of neuronal cells, may indicate a novel mechanism responsible for the pathogenesis in Parkinson disease.

Metabolic Biomarkers and Neurodegeneration: A Pathway Enrichment Analysis of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

“…Glycerol levels were decreased (Ahmed et al, 2009); however, propylene glycol and fatty acid levels were increased in PD (González-Domínguez et al, 2014b). These findings were supported by the previous studies that reported elevated levels of polyunsaturated fatty acids in the brain (Dias et al, 2013;Liu et al, 2008). Highly unsaturated fatty acids can cause lipid peroxidation and promote generation of toxic products under oxidative stress circumstances, which results in neural damage and promotes PD improvement.…”

Structural and Morphological Characterization of Aggregated Species of α-Synuclein Induced by Docosahexaenoic Acid

“…An important issue is to understand whether these chemical modifications are a requirement for the aggregation process. In the presence of lipids and fatty acids, these types of modifications, such as protein oxidations and aliphatic carbonyl adducts formation, have been observed both in vivo and in vitro (18,43,44). They are generated by radicals, hydroperoxides, and successively highly reactive aldehydes, produced by peroxidation of lipids.…”

The Impact of Oxidative Stress on Dopaminergic Neurotransmission

“…Moreover, DA is a substrate for the outer mitochondrial membrane-bound MAO, which stoichiometrically produces hydrogen peroxide (H 2 O 2 ) as well. The quinone derivative can react and form adducts with a variety of cellular proteins (such as α-synuclein, parkin, multiple mitochondrial proteins notably in complexes I and III, DATs) and DNA (Hastings 2009 ;Belluzzi et al 2012 ), as well as polyunsaturated fatty acids (Liu et al 2008 ). A further consequence is the induction of phase 4 mitochondrial respiration, with uncoupling from adenosine triphosphate (ATP) production and subsequent increase in ROS production.…”