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Neurotoxicity of levodopa: treatment-associated homocysteine increase

Arising from: Weiner WJ (2006) Levodopa—toxic or neuroprotective? Nat Clin Pract Neurol 2: 518–519 doi:10.1038/ncpneuro0293

The excellent Viewpoint on the role of levodopa (LD) in the treatment of Parkinson's disease (PD) by William Weiner focuses on the saga of harmful LD, which arose from research in animals and cell cultures and from the clinical observation of motor complications in LD-treated patients with PD, related to the short half-life of the drug.1 It should also be mentioned that the long-term application of LD is associated with an increase in homocysteine levels. This increase might accelerate PD progression, promote peripheral neurodegeneration and induce neuropsychiatric symptoms and vascular disease, as indicated by experimental and clinical data.2,3,4 Elevated homocysteine levels can result in impaired endothelial function and a subsequent reduction in mitochondrial energy metabolism. This in turn induces the generation of oxidative stress, the release of nitric oxide—an excitotoxic compound that mediates neuronal degeneration—and dysfunction of the basal ganglia circuit. These processes resemble the pathophysiological changes in patients with PD.1,2 Therapeutic approaches for the LD-mediated neurotoxic homocysteine increase include vitamin (folic acid) supplementation and LD application in combination with a strong, centrally acting inhibitor of catechol-O-methyltransferase (COMT; an enzyme involved in the metabolism of LD), which prolongs the half-life and increases the brain delivery of LD.5,6


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The authors thank Ralf Gold for his outstanding, stimulating contributions to the scientific discussion.

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Correspondence to Thomas Müller.

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Müller, T., Kuhn, W. Neurotoxicity of levodopa: treatment-associated homocysteine increase. Nat Rev Neurol 3, E1 (2007).

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