This paper is a new paper by Bush, Adlard, Finkelstein et al. It is a mouse study dealing also with iron.J Neurochem. 2019 Feb 4. doi: 10.1111/jnc.14676. [Epub ahead of print]L-DOPA modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha-synuclein mouse models of Parkinson'sdisease.
Billings JL1, Gordon SL2, Rawling T3, Doble PA4, Bush AI1, Adlard PA1, Finkelstein DI1, Hare DJ1,4,5.Abstract
Treatment with the dopamine (DA) precursor L-3,4-dihydroxyphenylalanine (L-DOPA) provides symptomatic relief arising from DA denervation in Parkinson'sdisease. Mounting evidence that DA autooxidation to neurotoxic quinones is involved in Parkinson'sdisease pathogenesis has raised concern about potentiation of oxidative stress by L-DOPA. The rate of DA quinone formation increases in the presence of excess redox-active iron (Fe), which is a pathological hallmark of Parkinson'sdisease. Conversely, L-DOPA has pH-dependent Fe-chelating properties, and may act to 'redox silence' Fe and partially allay DA autoxidation. We examined the effects of L-DOPA in three murine models of parkinsonian neurodegeneration: early-life Fe overexposure in wildtype (WT) mice, transgenic human (h)A53T mutant α-synuclein (α-syn) overexpression, and a combined 'multi-hit' model of Fe-overload in hA53T mice. We found that L-DOPA was neuroprotective and prevented age-related Fe accumulation in the substantia nigra pars compacta (SNc), similar to the mild-affinity Fe chelator clioquinol (CQ). Chronic L-DOPA treatment showed no evidence of increased oxidative stress in WT midbrain and normalised motor performance, when excess Fe was present. Similarly, L-DOPA also did not exacerbate protein oxidation levels in hA53T mice, with or without excess nigral Fe, and showed evidence of neuroprotection. The effects of L-DOPA in Fe-fed hA53T mice were somewhat muted, suggesting that Fe-chelation alone is insufficient to attenuate neuron loss in an animal model also recapitulating altered DA metabolism. In summary, we found no evidence in any of our model systems that L-DOPA treatment accentuated neurodegeneration, suggesting DA replacement therapy does not contribute to oxidative stress in the Parkinson'sdisease brain.
