Kinetic Modeling of pH-Dependent Oxidation of Dopamine by Iron and Its Relevance to Parkinson's Disease

Abstract

Parkinson's disease is the second most common neurodegenerative disease. While age is the most significant risk factor, the exact cause of this disease and the most effective approaches to mitigation remain unclear. It has long been proposed that dopamine may play a role in the pathology of Parkinson's disease in view of its ability to generate both protein-modifying quinones such as aminochrome and reactive oxygen species, especially in the presence of pathological iron accumulation in the primary site of neuron loss. Given the clinically measured acidosis of post-mortem Parkinson's disease brain tissue, the interaction between dopamine and iron was investigated over a pH range of 7.4 to 6.5 with emphasis on the accumulation of toxic quinones and generation of reactive oxygen species. Our results show that the presence of iron accelerates the formation of aminochrome with ferrous iron (Fe[II]) being more efficient in this regard than ferric iron (Fe[III]). Our results further suggest that a reduced aminochrome rearrangement rate coupled with an enhanced turnover rate of Fe[II] as a result of brain tissue acidosis could result in aminochrome accumulation within cells. Additionally, under these conditions, the enhanced redox cycling of iron in the presence of dopamine aggravates oxidative stress as a result of the production of damaging reactive species, including hydroxyl radicals.

l‐3,4‐dihydroxyphenylalanine (l‐DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha‐synuclein mouse models of Parkinson's disease

“…L-DOPA and DA were shown to suppress lipid peroxidation ex vivo, both in the presence and absence of Fe 3+ , though when a reducing agent was added lipid peroxidation products dramatically increased (Li et al 1995), suggesting an Fe[II]dependent process and supported in vitro studies demonstrating increased DA quinones production in a Fe-rich reducing environment (Sun et al 2018a). Both Fe[II] and Fe [III] can directly facilitate DA quinone production via their ability to form d-orbital bridges between DA and O 2 (Miller et al 1990) in multiple reactions with DA (Sun et al 2018b).…”

“…1), which is accelerated in the presence of DA by forming an unstable intermediary complex (Eq. 2) at pH 7.4 (Sun et al , 2018b:…”

Long‐Lasting Reactive Oxygen Species Generation by Porous Redox Mediator‐Potentiated Nanoreactor for Effective Tumor Therapy

“…[ 6 ] The imbalanced molecular transformation and electron transfer interplay between DA and Fe(II)/Fe(III) (0.77 V vs NHE) results in Fenton‐like chain reactions and long‐term accumulation of low‐dose •OH at low concentrations of intracellular substrates (i.e., H 2 O 2 ), and in turn, cell damage and degenerative neuronal diseases (e.g., Parkinson's disease). [ 7 ] The redox process [ 8 ] of Fe(III) ions by catechol usually starts with a fast step of chelation interaction as a result of the high affinity and the low solubility of Fe(III). After the slow one‐electron transfer from catechol to Fe(III), the regenerated Fe(II) can be released into the aqueous solution owing to the excellent water solubility of Fe(II).…”

A pH-eQTL interaction at the RIT2-SYT4 Parkinson’s disease risk locus in the substantia nigra

“…Using quantum chemical methods, Umek and colleagues determined that an acidic environment is required to prevent dopamine autoxidation (Umek et al 2018) . Kinetic modelling has also revealed that pH interactions with iron and dopamine could lead to oxidative stress (Sun et al 2018) . Caffeine consumption is associated with mild alkalosis (Tajima 2010) and a decreased risk of PD (Costa et al 2010) .…”