Why L-dopa, the drug used for treating Parkinson's disease, loses efficacy and causes dyskinesia as treatment progresses.

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Paradoxically, the therapy that improves the quality of life of patients with Parkinson's disease is the one that later contributes to the decline in their quality of life. Indeed over time, L-dopa (l-3,4-Dihydroxyphenylalanine), the main treatment for Parkinson's disease, loses its effectiveness and causes involuntary muscle movements and erratic movements and sometimes hallucinations. Although this effect is well identified, scientists did not understand why L-dopa accelerates the progression of the disease.

L-dopa and other pharmacological treatments for Parkinson's disease are designed to replace lost dopamine caused by degenerating nerve cells in the brain. Although dopamine cannot cross the blood-brain barrier, which allows substances such as water and oxygen to pass into the brain, L-dopa can. However, 99% of L-dopa is metabolized outside the brain, so it is given in combination with an enzyme inhibitor to prevent side effects such as nausea and heart problems, and allow more of the drug remains in the blood so as to be percolated through the blood-brain barrier. In this case, 5 to 10% of the ingested dose reaches the brain.

A team of researchers from the University of California, Irvine studied the molecular binding characteristics of L-dopa and related compounds using an optical technology called surface plasmon resonance to measure interactions between the drug and the target proteins. The results of the study were recently published in ACS Chemical Neuroscience. enter image description here

Their studies aimed to test whether continuous administration of L-dopa in animal models of Parkinson's disease is associated with increased iron accumulation in dopaminergic neurons in the brain and whether this accumulation depends on the binding of L-dopa to siderocalin.

The researchers also wanted to determine whether the complex can be detected in the blood of patients with Parkinson's disease. The relative amount of this complex would then serve as a biomarker to determine when it becomes appropriate to switch to new treatments for the disease.

Indeed l-DOPA chelates iron through its catechol group, is forming the l-DOPA:Fe complex. Siderophore-like catechol compounds are known to bind siderocalin (Scn)/lipocalin-2 to form stable siderophore:Fe:Scn complexes. Scn is up-regulated in the substantia nigra of PD patients and may play a role in the pathophysiology of PD.

Their results demonstrate that L-DOPA forms a stable complex with Scn in the presence of Fe3+.

Expressed more simply, this means that L-dopa and the protein siderocalin combine in the presence of iron to create a complex that can cause cellular iron overload, resulting in an imbalance between free radicals and antioxidants, as well as neuroinflammation.

The authors speculate that as Parkinson's disease progresses, this effect increases, inducing these negative side effects, while the dose needed to relieve disease symptoms increases, resulting in a window narrow therapy.

It remains that the effects of the enzyme inhibitor used to mitigate L-Dopa side effects, are not trivial either, but this study does not address this subject.

Moreover L-Dopa is not a panacea either, indeed its therapeutic effectiveness is different for different types of symptoms. Bradykinesia and rigidity are the most sensitive symptoms to L-Dopa administration, while tremors are less sensitive. Speech disorders, speech and swallowing disorders, postural instability and frozen gait are the least reactive symptoms.

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