Levodopa’s Ability to Bind Iron May Be Cause of Its Problems Over Time

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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L-dopa or levodopa, a standard treatment for Parkinson’s disease, forms a stable complex with iron and siderocalin, a protein involved in iron uptake by cells and found at higher levels in a brain region largely affected by Parkinson’s, a study shows.

These early findings suggest that the formation of this levodopa-iron-siderocalin complex may not only reduce levodopa’s effectiveness over time, but also promote a damaging iron overload within nerve cells, the researchers noted.

“This small L-dopa molecule is certainly mysterious,” Amal Alachkar, PhD, the study’s senior author and an associate professor at University of California-Irvine, said in a press release.

“We’re interested in unlocking L-dopa mysteries and, in particular, understanding how it acts as such a magic therapeutic agent and, at the same time, contributes to disease progression” with long-term use, Alachkar added.

The study, “Surface Plasmon Resonance Identifies High-Affinity Binding of l-DOPA to Siderocalin/Lipocalin-2 through Iron–Siderophore Action: Implications for Parkinson’s Disease Treatment,” was published in the journal ACS Chemical Neuroscience.

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Parkinson’s is caused by the progressive loss of dopamine — one of the brain’s major signaling molecules — due to the malfunction and death of dopamine-producing nerve cells in substantia nigra, a brain region involved in the control of voluntary movements.

Levodopa, a precursor of dopamine, is a mainstay Parkinson’s treatment. Despite its efficacy at easing motor symptoms, levodopa’s long-term use is associated with a need for higher and more frequent doses and the development of dyskinesia or involuntary jerky movements.

“Paradoxically, the exact therapy that improved the quality of life for tens of thousands of Parkinson’s patients is the one that contributes to the rapid decline in quality of life over time,” Alachkar said, adding that the “neural mechanisms” through which levodopa has been shown to speed “disease progression … are not very well understood.”

By analyzing the interactions between levodopa and other molecules, Alachkar and her team may have discovered this mechanism.

The levodopa molecule is known to contain a domain with iron-chelating properties, or the ability to tightly bind iron and prevent the toxic effects of extra free iron.

When bound to iron, the researchers found that levodopa forms a stable complex with siderocalin, a protein that strongly binds to iron-chelating molecules and is involved in iron transport into and within cells.

Notably, siderocalin has been shown to be at higher levels in the substantia nigra of people with Parkinson’s, where it may contribute to the disease by promoting to toxic levels iron accumulation within nerve cells.

Further analyzes found that levodopa’s iron-chelating domain was necessary but not sufficient to form a stable complex with siderocalin, suggesting the involvement of other molecular domains.

Researchers also found that levodopa, when bound to iron, starts to bind to siderocalin at doses lower than the maximum achieved in the blood of levodopa-treated patients. This suggests that some of the levodopa molecules in these patients will be forming this triple complex and not exerting their therapeutic effect.

These findings suggest that levodopa-iron “can readily form a stable complex with Scn [siderocalin] in the blood and brain environments, wherein Fe [iron] is abundant,” the researchers wrote.

Given that the levels of AADC, the enzyme that converts levodopa into dopamine, drop with time in the substantia nigra and related brain regions of Parkinson’s patients, more and more levodopa molecules reaching the brain may be sequestered to form levodopa-iron-siderocalin complexes.

“The formation of the L-dopa-siderocalin complex may play a role in decreasing efficacy by reducing the amount of free L-dopa available for dopamine synthesis in the brain,” Alachkar said.

This triple complex may also “facilitate the cellular uptake of Fe [iron] … causing cellular iron overload” and contributing to “iron-mediated oxidative stress and neuroinflammation in the substantia nigra,” the researchers wrote.

Oxidative stress is a type of cell damage resulting from an imbalance between the production of potentially harmful oxidant molecules — whose production can be promoted by excess iron — and the cells’ ability to clear them with antioxidants.

The researchers noted that further studies in animal models of Parkinson’s are needed to clarify the role of this levodopa complex.

They are now working with mouse disease models to assess whether continuous levodopa treatment is associated with iron accumulation in the substantia nigra, and if such accumulation depends on levodopa’s binding to siderocalin.

Researchers emphasized that future work should investigate whether the levodopa-iron-siderocalin complex can be detected in the blood of Parkinson’s patients, and whether it could serve as a biomarker of disease progression and a new treatment target.