Defective Levodopa Metabolism Linked to Waning Efficacy, Severe Adverse Effects

Defective metabolism of levodopa in the brain was associated with a decline in the drug's efficacy over time and the adverse effect of dyskinesia among patients with Parkinson disease.

Defective metabolism of the antiparkinsonian medication levodopa in the brain was associated with a decline in the drug's efficacy over time and the adverse effect of dyskinesia among patients with Parkinson disease (PD), according to study findings published last week in Science Advances.

Although highly effective in the early stages of PD, the researchers highlight that long-term usage of levodopa leads to abnormal involuntary movements, known as levodopa-induced dyskinesia (LID), which affects 10% of patients per year of treatment. Moreover, the benefits of levodopa, which serves as the current gold standard of care for PD, are greatly impacted by the presence of LID symptoms that remain poorly understood and can become debilitating.

Recently, the researchers say that advances in the field of mass spectrometry imaging (MSI) have established the potential of a novel technique in neuroscience, matrix-assisted laser desorption/ionisation MSI (MALDI-MSI), which comprehensively maps monoaminergic changes in the brain through its ability to detect a wide range of neuroactive compounds and metabolites in a single tissue section.

Utilizing MALDI-MSI, the researchers mapped the distribution of levodopa and monoaminergic pathways in nonhuman primate brain tissue, a process not previously possible. Primate brain tissue samples were placed into 2 groups and compared:

  • Group 1 included those suffering from motor complications caused by long-term levodopa treatment
  • Group 2 included a PD symptom–matched cohort receiving identical levodopa treatment, but who did not experience the motor adverse effects

When assessing both groups, the researchers found that everyone with motordis orders exhibited abnormally elevated levels of levodopa and its metabolite 3-O-methyldopa, a product created when levodopa is converted to dopamine. The presence of both variables was found in all the brain regions examined except for the striatum, which notably is thought to be involved in levodopa-induced movement disorders.

This finding indicates that brain mechanisms other than those already recognized may underlie disorders such as LID, which are likely triggered by a direct effect of levodopa or dopamine, or a combination of both, in some other part of the brain rather than the striatum.

Speaking on the impact of the study findings, lead author Professor Per Andrén, of the Department of Pharmaceutical Biosciences at Uppsala University, notes that this may lead to new strategies for treating advanced PD as results show levodopa, independent from dopamine, as a direct cause of LID.

"Although there seems to be a direct connection between levodopa and motor complications, the mechanism that brings about the involuntary movements is still unclear and subject to further research,” noted Andrén in a statement.

Reference

Andrén PE, Bezard E, Crossman AR, et al. Mass spectrometry imaging identifies abnormally elevated brain L-DOPA levels and extrastriatal monoaminergic dysregulation in L-DOPA-induced dyskinesia. Sci Adv. Published online January 6, 2021. doi:10.1126/sciadv.abe5948