Incorrect metabolism of Parkinson’s medicine within the mind mixed with critical unwanted effects

It was not previously known why the drug levodopa (L-dopa), which reduces motor symptoms in Parkinson’s disease, becomes less effective after a few years. A side effect that often occurs is involuntary movements. A Swedish-French collaboration led by Uppsala University has now been able to link the problems with the impaired metabolism of L-dopa in the brain. The study is published in Science Advances.

The results could lead to new strategies for the treatment of advanced Parkinson’s disease.

Professor Per Andrén from the Institute of Pharmaceutical Biosciences at Uppsala University. He and Dr. Erwan Bézard from the University of Bordeaux, France jointly led the study.

Parkinson’s disease (PD) is caused by the slow death of nerve cells that produce the key neurotransmitter, dopamine. This leads to the typical symptoms such as stiffness and tremors. Treatment with L-dopa, a precursor to dopamine, usually works very well at first. However, after a few years, the effects of each dose become increasingly short-lived. Unwanted side effects, such as a rapid change between stiffness and uncontrolled movements, which become more and more severe over time, are very common. Eventually, the benefits of L-dopa treatment are at risk and symptoms can become debilitating. It is unknown which neurochemical mechanisms cause these side effects. The involuntary movements are collectively referred to as “L-Dopa Induced Dyskinesia”.

Using a new method, “matrix-assisted laser desorption / ionization mass spectrometry imaging” (MALDI-MSI), the researchers were able to map numerous neurotransmitters and other biomolecules directly in non-human primate brain tissue, which was previously not possible. The samples came from a French biobank.

This enabled them to compare the brains of two groups of Parkinson’s animals in detail and identify the differences between them. One group suffered from motor complications caused by long-term treatment with L-dopa. The second group included people who had equal levels of PD symptoms and were receiving identical L-dopa treatment, but who had no motor side effects from the drug.

Abnormally elevated levels of L-dopa and 3-O-methyldopa were found in the motor impairment group. The latter, a metabolite, is a product made when L-dopa is converted into dopamine. This was seen in all brain regions studied, with the exception of the specific part of the brain known as the striatum, which is believed to be involved in L-dopa-induced movement disorders.

This suggests that brain mechanisms other than those previously recognized may be underlying motor disorders. Instead of originating from the striatum, these problems are most likely triggered by a direct action of L-dopa or dopamine, or a combination of both, in another part of the brain.

Although there appears to be a direct link between L-dopa and motor complications, the mechanism that causes the involuntary movements is still unclear and is still being explored. On the other hand, the new results show a direct role of L-Dopa in this motor disorder – independent of dopamine. And this indicates that L-Dopa can also act independently in the brain.

Professor Per Andrén

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Elva Fridjonsdottir et al., Mass Spectrometry Imaging Identifies Abnormally Elevated L-DOPA Levels in the Brain and Extrastriatal Monoaminergic Dysregulation in L-DOPA-Induced Dyskinesia, Science Advances. DOI: 10.1126 / sciadv.abe5948

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