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

Abstract

Treatment with the dopamine (DA) precursor l‐3,4‐dihydroxyphenylalanine (l‐DOPA) provides symptomatic relief arising from DA denervation in Parkinson's disease. Mounting evidence that DA autooxidation to neurotoxic quinones is involved in Parkinson'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's disease. 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 wild‐type mice, transgenic human (h)A53T mutant α‐synuclein (α‐syn) over‐expression, 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. 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's disease brain.

Animal Models for Parkinson’s Disease Research: Trends in the 2000s

“…Conducting research with this kind of animal model may provide new insight from the point of view of the dual-hit hypothesis [91,92]. In addition, such experiments may be useful in capturing the multifaceted nature of PD and could reveal the function of PD-related gene mutations [93]. We know that no toxin or genetic models completely reproduce the human PD.…”

“…In addition, comparing the various PD models may also be helpful to interpret the results. Some researchers have begun to use multiple models in one study [1,93,94,100,101,102]. Studies to clarify the pathology or to develop new treatment would be the main focus of these studies.…”

Experimental Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of the Evidence

“…Iron is also necessary for dopamine oxidation in neurons and microglia in the substantia nigra of PD patients. 20 Increase of iron deposition accelerates neuronal dopamine turnover, but generates synthesis of reactive oxygen species. This so-called "oxidative stress" promotes the aggregation and misfolding of proteins, particularly α-synuclein.…”

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

“…Furthermore, clioquinol improved cognition, motor functions and dopaminergic cell loss in transgenic A53T α-syn-overexpressing mice [439]. A concomitant treatment of clioquinol and L-DOPA in A53T α-syn-transgenic mice not only prevented neurodegeneration but also improve motor symptoms [440]. Q1 and Q4 are other 8-HQ derivatives that target specifically mitochondrial and cytosolic iron pools respectively.…”