Cytotoxicity of dopaminochrome in the mesencephalic cell line, MN9D, is dependent upon oxidative stress

Linsenbardt, Andrew J.; Wilken, Gerald H.; Westfall, Thomas C.; Macarthur, Heather

doi:10.1016/j.neuro.2009.07.006

Cited by 23 publications

(22 citation statements)

References 24 publications

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“…2). Aminochrome has been shown to be toxic to murine mesencephalic MN9D cells at concentrations as low as 50 μM (Linsenbardt et al, 2009). In the mesencephalic cell line, MN9, aminochrome induces caspase-independent apoptosis (Linsenbardt et al, 2012).…”

Section: Spontaneous Oxidation Of Catecholaminesmentioning

confidence: 99%

“…Anti-oxidant pre-treatment of animals or cells can attenuate or prevent neurotoxic effects of MPTP (Blanchet et al, 2008), MPP+ (Wu et al, 1994), levodopa (Lai & Yu, 1997; Peritore et al, 2012), DA (Lai & Yu, 1997; Wu & Johnson, 2011), and aminochrome (Linsenbardt et al, 2009). Metal ions, especially ions of iron, have long been suspected to participate in the pathogenetic process (Sofic et al, 1988; Ben-Shachar & Youdim, 1993; Youdim et al, 1993; Berg et al, 2001; Gotz et al, 2004; Jomova et al, 2010).…”

Section: Therapeutic Implications Of Catecholamine Autotoxicitymentioning

confidence: 99%

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Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

Goldstein

Kopin

Sharabi

2014

Pharmacology & Therapeutics

142

121

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Several neurodegenerative diseases involve loss of catecholamine neurons—Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of “autotoxicity”—inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the “catecholaldehyde hypothesis” for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis.

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Section: Spontaneous Oxidation Of Catecholaminesmentioning

confidence: 99%

Section: Therapeutic Implications Of Catecholamine Autotoxicitymentioning

confidence: 99%

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

Goldstein

Kopin

Sharabi

2014

Pharmacology & Therapeutics

142

121

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“…A potential explanation for the less-than-hoped-for results of MAO inhibition is secondary buildup of cytoplasmic DA and, consequently, augmented spontaneous oxidation of DA to form DA-quinone, which might offset beneficial effects of decreased DOPAL production. DA-quinone is toxic via spontaneous conversion to dopaminochrome (Linsenbardt et al, 2009;Aguirre et al, 2012) and reactivity with glutathione or cysteine to form 5-S-cysteinyl-dopamine (Cys-DA) (Montine et al, 1997;Spencer et al, 2002). Cys-DA provides a biomarker of DA auto-oxidation (Fornstedt et al, 1986;Carlsson and Fornstedt, 1991).…”

Section: Introductionmentioning

confidence: 99%

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

Goldstein

Jinsmaa

Sullivan

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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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.

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“…DA oxidation produces dopaminochrome (DAC) [10, 21, 42, 50, 56], a component of neuromelanin, the substance that pigments SNpc neurons [17, 60]. We have previously reported that DAC is cytotoxic to mesencephalic cells in an oxidative stress-dependent manner [35, 36]. …”

Section: Introductionmentioning

confidence: 99%

Direct intranigral injection of dopaminochrome causes degeneration of dopamine neurons

Touchette

Breckenridge

Wilken

et al. 2016

Neuroscience Letters

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Parkinson's disease (PD) is characterized by progressive neurodegeneration of nigrastriatal dopaminergic neurons leading to clinical motor dysfunctions. Many animal models of PD have been developed using exogenous neurotoxins and pesticides. Evidence strongly indicates that the dopaminergic neurons of the substantia nigra pars compacta (SNpc) are highly susceptible to neurodegeneration due to a number of factors including oxidative stress and mitochondrial dysfunction. Oxidation of DA to a potential endogenous neurotoxin, dopaminochrome (DAC), may be a potential contributor to the vulnerability of the nigrostriatal tract to oxidative insult. In this study, we show that DAC causes slow and progressive degeneration of dopaminergic neurons in contrast to 1-methyl-4-phenylpyridinium (MPP+), which induces rapid lesions of the region. The DAC model may be more reflective of early stresses that initiate the progressive neurodegenerative process of PD, and may prove a useful model for future neurodegenerative studies.

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Cytotoxicity of dopaminochrome in the mesencephalic cell line, MN9D, is dependent upon oxidative stress

Cited by 23 publications

References 24 publications

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

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

Direct intranigral injection of dopaminochrome causes degeneration of dopamine neurons

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