Occurrence and distribution of 5-S-cysteinyl derivatives of dopamine, dopa and dopac in the brains of eight mammalian species

Fornstedt, Bodil; Rosengren, E.; Carlsson, Arvid

doi:10.1016/0028-3908(86)90242-x

Cited by 154 publications

(95 citation statements)

References 2 publications

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“…Catecholaminergic cells are constantly coping with various, endogenously generated toxic compounds, which could have a direct effect on the generation of mtDNA deletion through their mutagenic properties, but may also lead to a reduced elimination of deleted mtDNA copies by disturbing quality control pathways. Indeed, cytosolic dopamine, the precursor of epinephrine, is readily converted into highly electrophilic dopamine quinones, which can covalently modify DNA [36,37], RNA and proteins [38,39]. Additionally, catecholamine degradation involving MAOs also generates molecules of highly neurotoxic potential [40,41,42], such as NH 3 , the aldehydes DOPAL (3,4-dihydroxyphenylacetaldehyde), DOPEGAL (3,4-dihydroxyphenylglycolaldeyde), MOPEGAL (3- methoxy-4-hydroxyphenyl-glycolaldehyde) and H 2 O 2 , which has been shown to cause oxidative damage to mtDNA and proteins [43,44].…”

Section: Discussionmentioning

confidence: 99%

Catecholamine Metabolism Induces Mitochondrial DNA Deletions and Leads to Severe Adrenal Degeneration during Aging

et al. 2016

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Background: Aging is a multifactorial process characterized by organ loss of function and degeneration, but the mechanisms involved remain elusive. We have shown recently that catecholamine metabolism drives the accumulation of mitochondrial DNA (mtDNA) deletions in dopaminergic cells, which likely contribute to their degeneration during aging. Here we investigated whether the well-documented degeneration and altered function of adrenals during aging is linked to catecholamine production in the medulla followed by accumulation of mtDNA deletions. Material and Methods: We analyzed adrenal medullary and cortical samples of both murine and human origin covering a wide range of ages for mtDNA deletion content, mtDNA copy number, mitochondrial and cellular integrity as well as aging-related tissue changes such as fibrosis. Results: Indeed, we demonstrate in mice and humans that the adrenal medulla accumulates a strikingly high amount of mtDNA deletions with age, causing mitochondrial dysfunction in the adrenal medulla, but also in the cortex, accompanied by apoptosis and, more importantly, by severe inflammation and remarkable fibrosis. Additionally, a concomitant and dramatic loss of medullary and cortical cells is observed in old animals. Conclusion: Our results show that accumulation of mtDNA deletions, and the ensuing mitochondrial dysfunction, is a hallmark of adrenal aging, further strengthening the hypothesis that catecholamine metabolism is detrimental to mtDNA integrity, mitochondrial function and cell survival. Moreover, the cell loss potentially induced by mitochondrial dysfunction could explain the decline in adrenal hormonal and steroidal secretion during aging.

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Section: Discussionmentioning

confidence: 99%

Catecholamine Metabolism Induces Mitochondrial DNA Deletions and Leads to Severe Adrenal Degeneration during Aging

et al. 2016

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“…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). In guinea pigs, MAO inhibition increases striatal and limbic system tissue contents of Cys-DA .…”

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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“…However, the pathways by which these factors lead to cell death and whether these factors are causative or a downstream symptom are unclear. In addition, the neurotransmitter dopamine itself is considered a major factor in PD pathology because it is easily oxidized into a variety of reactive metabolites (1,6,11,29,30). Both animal and cell culture models have been widely used to investigate possible mechanisms of cell death in dopaminergic neurons.…”

Section: Introduction Tmentioning

confidence: 99%

Microarray Expression Profiling Identifies Early Signaling Transcripts Associated with 6-OHDA-Induced Dopaminergic Cell Death

Holtz

Turetzky

O’Malley

2005

Antioxidants & Redox Signaling

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Occurrence and distribution of 5-S-cysteinyl derivatives of dopamine, dopa and dopac in the brains of eight mammalian species

Cited by 154 publications

References 2 publications

Catecholamine Metabolism Induces Mitochondrial DNA Deletions and Leads to Severe Adrenal Degeneration during Aging

Catecholamine Metabolism Induces Mitochondrial DNA Deletions and Leads to Severe Adrenal Degeneration during Aging

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

Microarray Expression Profiling Identifies Early Signaling Transcripts Associated with 6-OHDA-Induced Dopaminergic Cell Death

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