Catechol-O-methyltransferase inhibition protects against 3,4-dihydroxyphenylalanine (DOPA) toxicity in primary mesencephalic cultures: new insights into levodopa toxicity
| Autor: | Alexander Storch, Heinz Zettlmeisl, Markus Bareiss, Johannes Schwarz, Heike Blessing |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
S-Adenosylmethionine Cell Survival Dopamine Dopamine Agents COMT inhibitor Levodopa Cellular and Molecular Neuroscience chemistry.chemical_compound Benzophenones Mesencephalon Pregnancy Internal medicine medicine Animals Enzyme Inhibitors Rats Wistar Selenomethionine Cells Cultured Chromatography High Pressure Liquid Neurons Catechol-O-methyl transferase Tyrosine hydroxylase Chemistry Homovanillic acid Catechol O-Methyltransferase Inhibitors Stereoisomerism Cell Biology Dihydroxyphenylalanine nervous system diseases Rats medicine.anatomical_structure Endocrinology nervous system Toxicity Neuroglia Female Lipid Peroxidation medicine.drug |
| Zdroj: | Neurochemistry international. 42(2) |
| ISSN: | 0197-0186 |
| Popis: | Inhibition of catechol-O-methyltransferase (COMT) has protective effects on levodopa (L-DOPA), but not D-DOPA toxicity towards dopamine (DA) neurons in rat primary mesencephalic cultures [Mol. Pharmacol. 57 (2000) 589]. Here, we extend our recent studies to elucidate the mechanisms of these protective effects. Thus, we investigated the effects of all main L-DOPA/DA metabolites on survival of tyrosine hydroxylase immunoreactive (THir) neurons in primary rat mesencephalic cultures. 3-O-Methyldopa, homovanillic acid, dihydroxyphenyl acetate and 3-methoxytyramine had no effects at concentrations up to 300 micro M after 24h, whereas DA was more toxic than L-DOPA with toxicity at concentrations of >or=1 micro M. The coenzyme of COMT, S-adenosyl-L-methionine (SAM), and its demethylated product S-adenosylhomocystein caused no relevant alteration of THir neuron survival or L-DOPA toxicity. In contrast, inhibition of SAM synthesis by selenomethionine showed time- and dose-dependent increase of THir neuron survival, but did not affect L-DOPA toxicity. L-DOPA-induced lipid peroxidation in mesencephalic cultures was not modified by the COMT inhibitor Ro 41-0960 (1 micro M). Increased contamination of the cultures with glial cells attenuated L- and D-DOPA toxicity, but caused significant enhancement of protection by COMT inhibitors against L-DOPA toxicity only. Investigations of L-DOPA uptake in rat striatal cultures using HPLC revealed a significant reduction of extracellular L-DOPA concentrations by Ro 41-0960. Our data confirm that L-DOPA toxicity towards DA neurons is mediated by an autooxidative process, which is attenuated by glial cells. In addition, we demonstrate a second mechanism of L-DOPA toxicity in vitro mediated by a COMT- and glia-dependent pathway, which is blocked by COMT inhibitors, most likely due to enhanced glial uptake of L-DOPA. |
| Databáze: | OpenAIRE |
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