Examining Consequences of Levodopa’s Iron-Binding Ability in PD

A recent study proposes a hypothesis for why levodopa, the first-line therapy for treating the motor symptoms of Parkinson disease (PD), loses efficacy and causes dyskinesia, or off periods, the longer a patient stays on it.

University of California, Irvine (UCI) researchers studied the molecular binding characteristics of levodopa and related compounds using an optical technology called surface plasmon resonance to measure interactions between the drug and target proteins.

Findings demonstrate that levodopa and the protein siderocalin combine in the presence of iron to create a complex that may cause a cellular iron overload, leading to an imbalance between free radicals and antioxidants, as well as neuroinflammation in the brain, triggering dyskinesia, fluctuations in mobility and freezing episodes.

As PD progresses, lower doses of levodopa induce these negative side effects, while the dose required to alleviate disease symptoms increases, resulting in a narrow therapeutic window.

"This small L-dopa molecule is certainly mysterious," the study's co-corresponding author Amal Alachkar, PhD, associate professor of teaching in UCI's Department of Pharmaceutical Sciences, said in a statement. Researchers want to know how levodopa “acts as such a magic therapeutic agent and, at the same time, contributes to disease progression. 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."

The study was published in ACS Chemical Neuroscience.

Levodopa and other pharmacological treatments are designed to replace the lost dopamine caused by the degeneration of nerve cells in the brain. Although dopamine can't cross the blood-brain barrier, which lets substances such as water and oxygen pass into the brain, levodopa can. But 99% of the drug is metabolized outside the brain, so it is administered in combination with an enzyme inhibitor to increase the amount of the dose that reaches the brain to 5% to 10% and to prevent side effects such as nausea and heart problems.

Ongoing university studies are examining whether continuous levodopa administration in animal models of PD is associated with increased iron accumulation in the brain's dopaminergic neurons and if this accumulation depends on levodopa binding to siderocalin.

Researchers also want to determine whether the complex can be detected in the blood of patients, serving as a biomarker showing the correlation with their physical deterioration and as a target for novel treatments for the disease.

Reference

Alhassen S, Senel M, Alachachar A. Surface plasmon resonance identifies high-affinity binding of l-dopa to siderocalin/lipocalin-2 through iron–siderophore action: implications for Parkinson's disease treatment. ACS Chem Neurosci. Published online December 23, 2021. doi:10.1021/acschemneuro.1c00693