Oxidation and reactivity of 3,4-dihydroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative and movement disorder that involves specific loss of dopaminergic neurons in the substantia nigra of the brain. Exact causes of PD are unknown. However, cells affected in PD are centers of dopamine (DA) synthesis, storage, and metabolism, which implicate DA as an endogenous neurotoxin that contributes to PD. Furthermore, DA is known to undergo oxidation to radicals and quinones. These reactive species exert deleterious effects on cells through a variety of mechanisms that are relevant to the pathogenesis of PD.Another potential mechanism of toxicity for DA is metabolism to 3,4dihydroxyphenylacetaldehyde (DOPAL). This reactive metabolite is significantly more toxic than the parent DA. DOPAL has several demonstrated mechanisms of toxicity, including formation of protein-adducts via reaction with amine-type cellular nucleophiles. However, known toxicity mechanisms do not fully account for DOPAL's high toxicity. Oxidation of DOPAL to a reactive quinone or radical could help explain its high toxicity. Therefore, the hypothesis of this work is that DOPAL is capable of undergoing oxidation that leads to increased protein modification and nucleophilic reactivity.Experimentally, oxidation of DOPAL results in formation of a semi-quinone radical and an ortho-quinone, as confirmed by electron paramagnetic resonance spectroscopy and nuclear magnetic resonance spectroscopy, respectively. In agreement with the stated hypothesis, oxidation of DOPAL enhanced its ability to induce protein cross-linking of a model protein (glyceraldehyde 3-phosphate dehydrogenase) as indicated by polyacrylamide gel-electrophoresis. Also, the presence of anti-oxidants (ascorbate, N-acetyl cysteine) attenuated the reactivity of DOPAL with the model aminenucleophile N-acetyl lysine. These results indicate that DOPAL oxidation enhances both protein cross-linking and nucleophilic reactivity.

Copolymerization Kinetics of Dopamine Methacrylamide during PNIPAM Microgel Synthesis for Increased Adhesive Properties

“…60,61 During the microgel synthesis, the reaction mixture turned from white to orange-pink upon injection of DMA, which is also directly linked to the oxidation state of the catechol group: pink corresponds to the radical, yellow to a quinone and orange to a semiquinone formation. 48 The orange to pinkish color remained after freeze-drying of the microgels and additionally points out the incorporation of DMA.…”

“…The applied UV protection for MG mi3–4 did not affect the DMA reaction kinetics. In comparison to MG mi2 (same synthesis parameters, but no UV protection), the reaction mixture of MG mi3 and MG mi4 showed no color change upon the injection of DMA, which is a direct consequence of the absence of UV light …”

“…In comparison to MG mi2 (same synthesis parameters, but no UV protection), the reaction mixture of MG mi3 and MG mi4 showed no color change upon the injection of DMA, which is a direct consequence of the absence of UV light. 48 Additionally, auto-oxidation of DMA does not affect the DMA reaction kinetics. Even if DMA was exposed to oxygen for preparation purposes, the DMA reaction speed does not decrease with the increasing age of DMA (see SI Table S1).…”

“…DMA, dissolved in 5 mL of ethanol, was injected into the reactor at the time t DMA . After injection, the reaction mixture changed from white to orange-pink (suggesting the formation of semiquinones or radicals 48 ), except for the microgels MG mi3−4 . The reaction proceeded until the time t reac .…”