Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells
| Autor: | David S. Goldstein, Patti Sullivan, Yehonatan Sharabi, Courtney Holmes, Irwin J. Kopin, Yunden Jinsmaa |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Monoamine Oxidase Inhibitors 3 4-Dihydroxyphenylacetic acid Dopamine 3 4-Dihydroxyphenylacetaldehyde Pharmacology PC12 Cells 03 medical and health sciences chemistry.chemical_compound Neuropharmacology 0302 clinical medicine Clorgyline medicine Animals Humans Rasagiline Dose-Response Relationship Drug Dopaminergic Neurons Selegiline Dopaminergic Parkinson Disease Rats 030104 developmental biology Monoamine neurotransmitter chemistry 3 4-Dihydroxyphenylacetic Acid Molecular Medicine 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 356:484-493 |
| ISSN: | 1521-0103 |
| DOI: | 10.1124/jpet.115.230201 |
| Popis: | According to the catecholaldehyde hypothesis, the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to the loss of nigrostriatal dopaminergic neurons in Parkinson’s disease. Monoamine oxidase-A (MAO-A) catalyzes the conversion of intraneuronal dopamine to DOPAL and may serve as a therapeutic target. The “cheese effect”—paroxysmal hypertension evoked by tyramine-containing foodstuffs—limits clinical use of irreversible MAO-A inhibitors. Combined MAO-A/B inhibition decreases DOPAL production in rat pheochromocytoma PC12 cells, but whether reversible MAO-A inhibitors or MAO-B inhibitors decrease endogenous DOPAL production is unknown. We compared the potencies of MAO inhibitors in attenuating DOPAL production and examined possible secondary effects on dopamine storage, constitutive release, synthesis, and auto-oxidation. Catechol concentrations were measured in cells and medium after incubation with the irreversible MAO-A inhibitor clorgyline, three reversible MAO-A inhibitors, or the MAO-B inhibitors selegiline or rasagiline for 180 minutes. Reversible MAO-A inhibitors were generally ineffective, whereas clorgyline (1 nM), rasagiline (500 nM), and selegiline (500 nM) decreased DOPAL levels in the cells and medium. All three drugs also increased dopamine and norepinephrine, decreased 3,4-dihydroxyphenylalanine, and increased cysteinyl-dopamine concentrations in the medium, suggesting increased vesicular uptake and constitutive release, decreased dopamine synthesis, and increased dopamine spontaneous oxidation. In conclusion, clorgyline, rasagiline, and selegiline decrease production of endogenous DOPAL. At relatively high concentrations, the latter drugs probably lose their selectivity for MAO-B. Possibly offsetting increased formation of potentially toxic oxidation products and decreased formation of DOPAL might account for the failure of large clinical trials of MAO-B inhibitors to demonstrate slowing of neurodegeneration in Parkinson’s disease. |
| Databáze: | OpenAIRE |
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