Abstract
Background
Elevated plasma total homocysteine (tHcy) appeared in levodopa/dopadecarcoxylase inhibitor (DDI) treated patients with Parkinson’s disease (PD). One therapeutic approach for tHcy reduction is vitamine supplementation, since folic acid and cobalamine catalyse and enhance metabolism of tHcy to methionine. A further therapeutic alternative is inhibition of catechol-O-methyltransfrase (COMT) on a regular basis, when levodopa/DDI treatment is performed.
Methods
We measured the concentrations of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), tHcy, levodopa and 3-O-methyldopa in plasma of 13 levodopa treated PD patients before first drug intake at 0600 hours. Blood samples were taken before and after 2 days of additional application of the centrally acting catechol-O-methyltransferase inhibitor tolcapone 100 mg t.i.d.
Results
Plasma levels of SAH [day 1: 48.32±22.52, 23.92–98.25 (mean±SD, range; μmol/l); day 3: 37.72±15.84, 23.4–61.89; p=0.01] and tHcy (day 1: 13.88±5.62, 7.63–24.81; day 3: 11.38±4.44, 5.98–20.45; p=0.04) significantly reduced. Plasma levels of levodopa did not significantly (p=0.17) increase, whereas 3-OMD concentrations significantly (p=0.0002) reduced after additional tolcapone intake. There was no significant change of SAM plasma levels (p=0.22).
Conclusion
Our prospective trial shows, that COMT inhibition with tolcapone lowers tHcy synthesis. Tolcapone may also possess beside its proven, occasional, hepatotoxic potency also beneficial effects via decrease of SAH and tHcy. This may hypothetically reduce homocysteine mediated progress of neuronal degeneration and the risk for onset of dementia, vascular disease and polyneuropathy in levodopa treated PD patients in the long term.
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References
Ceravolo R, Piccini P, Bailey DL, Jorga KM, Bryson H, Brooks DJ (2002) 18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson’s disease. Synapse 43:201–207
Huang G, Dragan M, Freeman D, Wilson JX (2005) Activation of catechol-O-methyltransferase in astrocytes stimulates homocysteine synthesis and export to neurons. Glia 51:47–55
Isobe C, Murata T, Sato C, Terayama Y (2005) Increase of total homocysteine concentration in cerebrospinal fluid in patients with Alzheimer’s disease and Parkinson’s disease. Life Sci 77:1836–1843
Lamberti P, Zoccolella S, Iliceto G, Armenise E, Fraddosio A, de Mari M et al (2005) Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson’s disease patients. Mov Disord 20:69–72
Lee ES, Chen H, Soliman KF, Charlton CG (2005) Effects of homocysteine on the dopaminergic system and behavior in rodents. Neurotoxicology 26:361–371
Matsubara K, Aoyama K, Suno M, Awaya T (2002) N-methylation underlying Parkinson’s disease. Neurotoxicol Teratol 24:593–598
Miller JW, Shukitt-Hale B, Villalobos-Molina R, Nadeau MR, Selhub J, Joseph JA (1997) Effect of L-Dopa and the catechol-O-methyltransferase inhibitor Ro 41- 0960 on sulfur amino acid metabolites in rats. Clin Neuropharmacol 20:55–66
Müller T, Renger K, Kuhn W (2004) Levodopa associated homocysteine increase and sural axonal neurodegeneration. Arch Neurol 61:657–660
Müller T, Kuhn W, Przuntek H (1993) Therapy with central active catechol-O-methyltransferase (COMT)-inhibitors: is addition of monoamine oxidase (MAO)-inhibitors necessary to slow progress of neurodegenerative disorders? J Neural Transm Gen Sect 92:187–195
Müller T, Werne B, Fowler B, Kuhn W (1999) Nigral endothelial dysfunction, homocysteine, and Parkinson’s disease [letter]. Lancet 354:126–127
Müller T, Woitalla D, Hauptmann B, Fowler B, Kuhn W (2001) Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson’s disease. Neurosci Lett 308:54–56
Müller T, Woitalla D, Kuhn W (2003) Benefit of folic acid supplementation in parkinsonian patients treated with levodopa. J Neurol Neurosurg Psychiatry 74:549
Nakaso K, Yasui K, Kowa H, Kusumi M, Ueda K, Yoshimoto Y et al (2003) Hypertrophy of IMC of carotid artery in Parkinson’s disease is associated with L-DOPA, homocysteine, and MTHFR genotype. J Neurol Sci 207:19–23
O’Suilleabhain PE, Bottiglieri T, Dewey RB Jr, Sharma S, Diaz-Arrastia R (2004) Modest increase in plasma homocysteine follows levodopa initiation in Parkinson’s disease. Mov Disord 19:1403–1408
Onofrj M, Thomas A, Iacono D, Di Iorio A, Bonanni L (2001) Switch-over from tolcapone to entacapone in severe Parkinson’s disease patients. Eur Neurol 46:11–16
Ostrem JL, Kang GA, Subramanian I, Guarnieri M, Hubble J, Rabinowicz AL et al (2005) The effect of entacapone on homocysteine levels in Parkinson disease. Neurology 64:1482
Russ H, Müller T, Woitalla D, Rahbar A, Hahn J, Kuhn W (1999) Detection of tolcapone in the cerebrospinal fluid of parkinsonian subjects. Naunyn Schmiedebergs Arch Pharmacol 360:719–720
Valkovic P, Benetin J, Blazicek P, Valkovicova L, Gmitterova K, Kukumberg P (2005) Reduced plasma homocysteine levels in levodopa/entacapone treated Parkinson patients. Parkinsonism Relat Disord 11:253–256
Zoccolella S, Lamberti P, Armenise E, de Mari M, Lamberti SV, Mastronardi R et al (2005) Plasma homocysteine levels in Parkinson’s disease: role of antiparkinsonian medications. Parkinsonism Relat Disord 11:131–133
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Müller, T., Kuhn, W. Tolcapone decreases plasma levels of S-adenosyl-L-homocysteine and homocysteine in treated Parkinson’s disease patients. Eur J Clin Pharmacol 62, 447–450 (2006). https://doi.org/10.1007/s00228-006-0132-0
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DOI: https://doi.org/10.1007/s00228-006-0132-0