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

Treatment with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (l-DOPA) provides symptomatic relief arising from DA denervation in Parkinson&#39;s disease. Mounting evidence that DA autooxidation to neurotoxic quinones is involved in Parkinson&#39;s disease 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&#39;s disease. Conversely, l-DOPA has pH-dependent Fe-chelating properties, and may act to &#39;redox silence&#39; 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 wild-type mice, transgenic human (h)A53T mutant α-synuclein (α-syn) over-expression, and a combined &#39;multi-hit&#39; 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. Chronic l-DOPA treatment showed no evidence of increased oxidative stress in wild-type midbrain and normalized 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&#39;s disease brain.