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Research ArticleArticle

Catechol-O-methyltransferase Inhibition Attenuates Levodopa Toxicity in Mesencephalic Dopamine Neurons

Alexander Storch, Heike Blessing, Markus Bareiss, Sinje Jankowski, Zao Dung Ling, Paul Carvey and Johannes Schwarz
Molecular Pharmacology March 2000, 57 (3) 589-594; DOI: https://doi.org/10.1124/mol.57.3.589
Alexander Storch
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Heike Blessing
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Markus Bareiss
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Sinje Jankowski
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Zao Dung Ling
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Paul Carvey
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Johannes Schwarz
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Abstract

Inhibition of catechol-O-methyltransferase (COMT; EC 2.1.1.6) is a new therapeutic strategy in the treatment of Parkinson's disease. However, nothing is known about the effects of COMT inhibition on levodopa (l-dopa)-induced toxicity in dopamine (DA) neurons. Therefore we evaluated the effects of the selective COMT inhibitors Ro 41-0960, OR-486, and tolcapone alone and in combination with l-dopa in primary mesencephalic cultures from rat. Neither COMT inhibitor affected the growth of tyrosine hydroxylase immunoreactive (THir) cells with concentrations up to 10 μM when studied alone. However, Ro 41-0960 reduced thel-dopa-induced THir cell loss after 24 h in a dose-dependent manner, shifting the TD50 value from 21 μM in the absence to 71 μM in the presence of 1 μM Ro 41-0960 (P < .01) without affecting survival of non-DA neurons. OR-486 and the clinically used COMT inhibitor tolcapone showed similar effects. In contrast, toxicity induced by d-dopa was not altered by COMT inhibitors. Furthermore, the primary metabolite of l-dopa formed by COMT, 3-O-methyldopa, and the methyl group donorS-adenosyl-l-methionine used by COMT did not alter THir neuron survival and l-dopa-induced toxicity, respectively, with concentrations up to 100 μM. These data demonstrate that COMT inhibition attenuates l-dopa toxicity toward DA neurons in vitro, but probably not by preventing 3-O-methyldopa production or cellularS-adenosyl-l-methionine depletion.

Footnotes

    • Received July 30, 1999.
    • Accepted December 1, 1999.
  • Send reprint requests to: Alexander Storch, M.D., University of Ulm Medical School, Department of Neurology, Oberer Eselsberg 45, 89081 Ulm, Germany. E-mail:alexander.storch{at}medizin.uni-ulm.de

  • ↵1 Present address: California Institute of Technology, Division of Biology, Pasadena, CA.

  • This study was supported by the University of Ulm Medical School Research Foundation and the Pharmacia & Upjohn Company, Erlangen, Germany. A preliminary account of these observations was presented in abstract form at the Annual Meeting of the American Academy of Neurology, April 22, 1999, Toronto, Canada.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (3)
Molecular Pharmacology
Vol. 57, Issue 3
1 Mar 2000
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Research ArticleArticle

Catechol-O-methyltransferase Inhibition Attenuates Levodopa Toxicity in Mesencephalic Dopamine Neurons

Alexander Storch, Heike Blessing, Markus Bareiss, Sinje Jankowski, Zao Dung Ling, Paul Carvey and Johannes Schwarz
Molecular Pharmacology March 1, 2000, 57 (3) 589-594; DOI: https://doi.org/10.1124/mol.57.3.589

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Research ArticleArticle

Catechol-O-methyltransferase Inhibition Attenuates Levodopa Toxicity in Mesencephalic Dopamine Neurons

Alexander Storch, Heike Blessing, Markus Bareiss, Sinje Jankowski, Zao Dung Ling, Paul Carvey and Johannes Schwarz
Molecular Pharmacology March 1, 2000, 57 (3) 589-594; DOI: https://doi.org/10.1124/mol.57.3.589
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