Paraquat-Melanin Redox-Cycling: Evidence from Electrochemical Reverse Engineering.

Parkinson's disease is a neurodegenerative disorder associated with oxidative stress and the death of melanin-containing neurons of the substantia nigra. Epidemiological evidence links exposure to the pesticide paraquat (PQ) to Parkinson's disease and this link has been explained by a redox-cycling mechanism that induces oxidative stress. Here, we used a novel electrochemistry-based reverse engineering methodology to test the hypothesis that PQ can undergo reductive redox-cycling with melanin. In this method, (i) insoluble model melanin (from Sepia) was entrapped in a non-conducting hydrogel film adjacent to an electrode, (ii) the film-coated electrode was immersed in solutions containing PQ (putative redox-cycling reductant) and a redox-cycling oxidant (ferrocene dimethanol), (iii) sequences of input potentials (i.e., voltages) were imposed to the underlying electrode to systematically engage reductive and oxidative redox-cycling, and (iv) output response currents were analyzed for signatures of redox-cycling. The response characteristics of the PQ-melanin system to three separate input potential sequences support the hypothesis that PQ can directly donate electrons to melanin. This observation of PQ-melanin redox-interactions demonstrates an association between two components that have been individually linked to oxidative stress and Parkinson's disease. Potentially, melanin's redox-activity could be an important component in understanding the etiology of neurological disorders such as Parkinson's disease.