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Dopaminergic neurotoxicity of homocysteine and its derivatives in primary mesencephalic cultures

  • Chapter
Focus on Extrapyramidal Dysfunction

Part of the book series: Journal of Neural Transmission. Supplementa ((NEURAL SUPPL,volume 68))

Summary

Levodopa and dopamine are metabolized to 3-O-methyldopa and 3-methoxytyramine, respectively, by the enzyme catechol-O-methyltransferase (COMT) leading to the production of the demethylated cofactor S-adenosylhomocysteine (SAH) and subsequently homocysteine (HC). Indeed, treatment of Parkinson’s disease (PO) patients with levodopa leads to increased HC blood levels. Therefore, HC is discussed to be involved in the pathogenesis of PD as well as in enhanced progression of PD in patients treated with levodopa. Here we investigated the toxicity of HC and its derivatives SAH, homocysteic acid (HCA) and cysteic acid (CA) on tyrosine hydroxylase (TH)-positive neurons in primary mesencephalic cultures from rat in vitro. Furthermore, we evaluated the toxicity of HC on cultures stressed with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Incubation with HC or HCA did not result in significant effects on TH-positive neuron survival with concentrations up to 1mM, but led to morphological changes of TH-positive cells with significantly fewer and shorter neurites at concentrations of ≥100 μM after 48 h. In contrast, SAH and CA were toxic at concentrations of 100 >M after 48 h. Furthermore, MPP+ showed strong toxicity towards TH-positive cells after 48 h (half-maximal toxic concentration: 20 μM), whereas eo-incubation with HC for 24 or 48 h did not further alter TH-positive cell survival. Taken together, our results do not demonstrate relevant dopaminergic toxicity of HC in vitro, and therefore HC is most likely not involved in the pathogenesis of PO or in accelerating the progression of PO by levodopa.

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Authors and Affiliations

  1. Department of Neurology, University of Ulm, Germany

    I. Heider, V. Lehmensiek, Th. Lenk & A. Storch M.D.

  2. Department of Neurology, Ruhr University of Bochum, Germany

    Th. Müller

  3. Department of Neurology, Technical University of Dresden, Fetscherstrasse 74, D-01307, Dresden, Germany

    A. Storch M.D.

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  1. I. Heider
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Editors and Affiliations

  1. Neurologische Klinik, St. Josef Hospital, Gudrunstraße 56, 44791, Bochum, Germany

    Th. Müller

  2. Klinik und Poliklinik für Psychiatrie und Psychotherapie, Füchsleinstraße 15, 97080, Würzburg, Germany

    P. Riederer

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Heider, I., Lehmensiek, V., Lenk, T., Müller, T., Storch, A. (2004). Dopaminergic neurotoxicity of homocysteine and its derivatives in primary mesencephalic cultures. In: Müller, T., Riederer, P. (eds) Focus on Extrapyramidal Dysfunction. Journal of Neural Transmission. Supplementa, vol 68. Springer, Vienna. https://doi.org/10.1007/978-3-7091-0579-5_1

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  • DOI: https://doi.org/10.1007/978-3-7091-0579-5_1

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