Abstract
Chronic levodopa (LD)/dopadecarboxylase inhibitor (DDI) increases homocysteine generation as side reaction of O-methylation. Aim was to investigate the impact of the peripheral COMT inhibitor entacapone (EN) on plasma concentrations of homocysteine, LD and 3-O-methyl-dopa (3-OMD). Patients with Parkinson’s disease (PD) received on two consecutive days in a standardised fashion one single dose of 200 mg retarded release LD/carbidopa (CD) or of 150 mg LD/CD/EN, since both were shown to have simultaneous pharmacokinetic LD behaviour. Homocysteine increased after retarded release LD/CD application, but not following LD/CD/EN intake. Homocysteine was lower during the LD/CD/EN condition 80 min after baseline when compared with its levels after LD/CD administration. LD levels simultaneously rose on both days. 3-OMD concentrations did not change. Acute LD/CD application caused a rise of homocysteine levels, which was prevented by LD/CD/EN intake. Therefore, peripheral COMT inhibition may have a beneficial effect on putative, controversially debated components of homocysteine-related progression of PD.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Austin RC, Lentz SR, Werstuck GH (2004) Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ 11(Suppl 1):S56–S64
Ben Shlomo Y, Marmot MG (1995) Survival and cause of death in a cohort of patients with parkinsonism: possible clues to aetiology? J Neurol Neurosurg Psychiatry 58:293–299
Bots ML, Launer LJ, Lindemans J, Hoes AW, Hofman A, Witteman JC, Koudstaal PJ, Grobbee DE (1999) Homocysteine and short-term risk of myocardial infarction and stroke in the elderly: the Rotterdam Study. Arch Intern Med 159:38–44
Faucheux BA, Bonnet AM, Agid Y, Hirsch EC (1999) Blood vessels change in the mesencephalon of patients with Parkinson’s disease. Lancet 353:981–982
Gorell JM, Johnson CC, Rybicki BA (1994) Parkinson’s disease and its comorbid disorders: an analysis of Michigan mortality data, 1970 to 1990. Neurology 44:1865–1868
Hassin-Baer S, Cohen O, Vakil E, Sela BA, Nitsan Z, Schwartz R, Chapman J, Tanne D (2006) Plasma homocysteine levels and Parkinson disease: disease progression, carotid intima-media thickness and neuropsychiatric complications. Clin Neuropharmacol 29:305–311
Lamberti P, Zoccolella S, Iliceto G, Armenise E, Fraddosio A, de MM, Livrea P (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
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 (2008) Role of homocysteine in the treatment of Parkinson’s disease. Expert Rev Neurother 8:957–967
Müller T, Kuhn W (2006) Tolcapone decreases plasma levels of S-adenosyl-l-homocysteine and homocysteine in treated Parkinson’s disease patients. Eur J Clin Pharmacol 62:447–450
Müller T, Kuhn W (2009) Homocysteine levels after acute levodopa intake in patients with Parkinson’s disease. Mov Disord [Epub ahead of print]
Müller T, Renger K, Kuhn W (2004) Levodopa-associated increase of homocysteine levels and sural axonal neurodegeneration. Arch Neurol 61:657–660
Müller T, Ander L, Kolf K, Woitalla D, Muhlack S (2007) Comparison of 200 mg retarded release levodopa/carbidopa—with 150 mg levodopa/carbidopa/entacapone application: pharmacokinetics and efficacy in patients with Parkinson’s disease. J Neural Transm 114:1457–1462
Nakaso K, Yasui K, Kowa H, Kusumi M, Ueda K, Yoshimoto Y, Takeshima T, Sasaki K, Nakashima K (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
Nissinen E, Nissinen H, Larjonmaa H, Vaananen A, Helkamaa T, Reenila I, Rauhala P (2005) The COMT inhibitor, entacapone, reduces levodopa-induced elevations in plasma homocysteine in healthy adult rats. J Neural Transm 112:1213–1221
O’Suilleabhain PE, Sung V, Hernandez C, Lacritz L, Dewey RB Jr, Bottiglieri T, Diaz-Arrastia R (2004) Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations. Arch Neurol 61:865–868
O’Suilleabhain PE, Oberle R, Bartis C, Dewey RB Jr, Bottiglieri T, az-Arrastia R (2006) Clinical course in Parkinson’s disease with elevated homocysteine. Parkinsonism Relat Disord 12:103–107
Ozer F, Meral H, Hanoglu L, Aydemir T, Yilsen M, Cetin S, Ozturk O, Seval H, Koldas M (2006) Plasma homocysteine levels in patients treated with levodopa: motor and cognitive associations. Neurol Res 28:853–858
Postuma RB, Espay AJ, Zadikoff C, Suchowersky O, Martin WR, Lafontaine AL, Ranawaya R, Camicioli R, Lang AE (2006) Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: a randomized controlled study. Neurology 66:1941–1943
Reitz C, Trenkwalder C, Kretzschmar K, Roesler A, v Eckardstein A, Berger K (2006) Relation of cerebral small-vessel disease and brain atrophy to mild parkinsonism in the elderly. Mov Disord 21:1914–1919
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
Woitalla D, Kuhn W, Müller T (2004) MTHFR C677T polymorphism, folic acid and hyperhomocysteinemia in levodopa treated patients with Parkinson’s disease. J Neural Transm Suppl 1:5–20
Zesiewicz TA, Wecker L, Sullivan KL, Merlin LR, Hauser RA (2006) The controversy concerning plasma homocysteine in Parkinson disease patients treated with levodopa alone or with entacapone: effects of vitamin status. Clin Neuropharmacol 29:106–111
Zoccolella S, Lamberti P, Armenise E, de MM, Lamberti SV, Mastronardi R, Fraddosio A, Iliceto G, Livrea P (2005a) Plasma homocysteine levels in Parkinson’s disease: role of antiparkinsonian medications. Parkinsonism Relat Disord 11:131–133
Zoccolella S, Lamberti P, Iliceto G, Diroma C, Armenise E, Defazio G, Lamberti SV, Fraddosio A, de MM, Livrea P (2005b) Plasma homocysteine levels in l-dopa-treated Parkinson’s disease patients with cognitive dysfunctions. Clin Chem Lab Med 43:1107–1110
Acknowledgments
We thank Lema Ander, Ulrike Beckmann, Marion Frickmann, Christa Kraushaar-Szesny, Kira Kolf, Christine Stamm, Tanja Steiner and Dirk Woitalla for technical assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Müller, T., Muhlack, S. Peripheral COMT inhibition prevents levodopa associated homocysteine increase. J Neural Transm 116, 1253–1256 (2009). https://doi.org/10.1007/s00702-009-0275-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-009-0275-0