The study with that finding, “L-DOPA modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha-synuclein mouse models of Parkinson’s disease,” was published in the Journal of Neurochemistry.
L-DOPA is sill the primary pharmacological treatment for Parkinson’s disease motor symptoms. However, while the therapy provides symptom relief immediately following the onset of motor symptoms, during later stages of the disease certain non L-DOPA-responsive symptoms emerge that contribute to the rapid decline in quality of life.
Conflicting evidence also suggests the therapy may further damage dopamine-producing neurons due to the overproduction of reactive oxygen species, a molecular phenomenon known as oxidative stress.
Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or reactive oxygen species, are harmful to the cells and are associated with a number of diseases, including Parkinson’s disease.
Several studies have established an association between iron build-up and both aging and neurodegenerative disorders like Parkinson’s disease. Apart from loss of dopamine-producing neurons, Parkinson’s also is characterized by pronounced iron accumulation in two brain regions: the globus pallidus and the substantia nigra.
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It has been suggested that free iron molecules can induce dopamine oxidation and thus contribute to Parkinson’s disease development. Nonetheless, the exact mechanism of iron-induced dopaminergic degeneration is still unclear.
“Considering the substantial conflicts in the literature regarding whether L -DOPA is either neurotoxic or protective, and that [iron] has multiple well-established roles in both normal [dopamine] metabolism and neurotoxic oxidation,” researchers from the University of Melbourne, Australia, examined the effects of L -DOPA administration in three mouse models of Parkinson’s disease.
Mice fed with an iron solution from 10 to 17 days of age — mimicking early-life iron overexposure to accelerated age-related accumulation; a mouse model of Parkinson’s disease which over-expresses human A53T mutation (hA53T) in the alpha-synuclein protein, mimicking disrupted dopamine metabolism; and a mouse model combining these two experimental paradigms, i.e., hA53T transgenic iron-fed mice.
Animals were given L-DOPA in their drinking water from three to eight months of age. Researchers analyzed the therapy’s effect on brain iron levels, nerve cell numbers and motor function prior to the equivalent onset of clinical symptoms, in comparison to mice fed with clioquinol spiked food for the same period of time.
Clioquinol is a compound that binds to iron molecules suppressing their (harmful) chemical activity. Studies demonstrate clioquinol is beneficial in animal models of three neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.
Results revealed L-DOPA did not increase neurotoxicity in any of the mouse models and prevented age-related iron accumulation in the substantia nigra, much like clioquinol.
In addition, researchers observed a potential neuroprotective effect, as in both the iron overload and the hA53T mouse models L-DOPA treatment significantly reduced iron levels in the substantia nigra, decreased protein carbonyls (biomarkers of oxidative stress), and prevented neurodegeneration.
“Chronic L -DOPA treatment showed no evidence of increased oxidative stress in [normal mice] midbrain and [normalized] motor performance, when excess [iron] was present,” researchers wrote.
Additionally, L-DOPA did not increase protein oxidation levels in hA53T mice, with or without excess iron accumulation in the substantia nigra, and showed evidence of neuroprotection.
At eight months, total iron levels did not increase in hA53T mice that did not receive L-DOPA, suggesting the mutant alpha-synuclein does not itself trigger harmful iron accumulation.
“When challenged with excess [iron] during a critical window of neurodevelopment [10-17 days of age], hA53T mice showed the expected increase in nigral [iron]. Interestingly, excess [iron] did not worsen or accelerate neuropathology,” researchers wrote.
Similar to clioquinol, L -DOPA was able to mitigate oxidative damage from excessive iron accumulation. This effect was not as pronounced in hA53T expressing mice, which are more susceptible to oxidative damage from iron exposure.
These findings suggest that alpha-synuclein dysfunction could be behind iron-mediated dopamine oxidation, with the latter being an early sign of parkinsonian neurodegeneration.
“We found no evidence in any of our model systems that L-DOPA treatment accentuated neurodegeneration, suggesting [dopamine] replacement therapy does not contribute to oxidative stress in the Parkinson’s disease brain,” researchers concluded.