Comparison of Monoamine Oxidase Inhibitors in Decreasing Production of the Autotoxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde in PC12 Cells

Abstract

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.

Elevated cerebrospinal fluid ratios of cysteinyl-dopamine/3,4-dihydroxyphenylacetic acid in parkinsonian synucleinopathies

“…Consistent with this view, MAO inhibition increases striatal Cys-DA content in guinea pigs [29] and endogenous Cys-DA production in PC12 cells [30]. None of the patients in this study was on an MAO inhibitor.…”

3,4-Dihydroxyphenylethanol (Hydroxytyrosol) Mitigates the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells

“…In this study the MAO inhibitors clorgyline, rasagiline, and selegiline decreased endogenous levels of the autotoxic dopamine metabolite DOPAL in PC12 cells but concurrently increased spontaneous oxidation of dopamine as indicated by Cys-DA levels, confirming the findings in a recent study [11]. The main new findings reported here are that DOPET decreases DOPAL and Cys-DA levels and prevents the increases in Cys-DA levels seen with MAO inhibition.…”

“…The cells and medium were assayed for contents of catechols by batch alumina extraction followed by liquid chromatography with electrochemical detection in our laboratory [20]. Levels in the cells and medium were summed and expressed as pmol/well.…”

“…Under steady state conditions the rate of accumulation of DOPA equals the rate of DOPA synthesis due to intracellular TH activity [20]. …”

“…Inhibition of monoamine oxidase (MAO), by decreasing DOPAL production, should therefore slow the neurodegeneration [1]. MAO inhibition, however, secondarily builds up cytoplasmic dopamine, resulting in increased spontaneous oxidation to dopamine-quinone [2, 3] and formation of potentially toxic compounds [4–7], including 5-S-cysteinyl-dopamine (Cys-DA) [8–11]. Harmful effects of augmented spontaneous dopamine oxidation during MAO inhibition might offset the beneficial effects of decreasing DOPAL production.…”