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.
Highlights
Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease (Guttmacher et al, 2003)
(i) generation of DAC and hydrogen peroxide (H2O2) are used to constrain the rate constants for transformation of DA both in the absence and presence of iron including those for the oxidation of DA and leukoaminochrome (DAL) and cyclization of DA o-quinone (DAQ); (ii) decay of Fe[II] and formation of Fe-DA complexes in the presence of O2 are used to constrain the rate constant for the DA-induced transformation of Fe; and (iii) formation of Fe[III]-DA complexes in the absence of O2 is used to constrain the rate constants for mono-complex formation, DAinduced reductive dissolution of ferrihydrite as well as the dynamic equilibrium between the mono- and bis-complexes
Highlighting the versatility of Fe redox activity and why it is tightly regulated under normal physiological conditions, these results suggest that the oxidative load in a dopaminergic neuron arising from Fe-mediated hydroxyl radical (OH) production at basal H2O2 levels are somewhat mitigated by the concomitant oxidation of Fe[II], effectively sequestering Fe in the ferric state, which is less active with respect to neurotoxic DAC production
Summary
Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease (Guttmacher et al, 2003).
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