Dopamine–melanin induces apoptosis in PC12 cells; possible implications for the etiology of Parkinson's disease

Offen, Daniel; Ziv, Ilan; Barzilai, Ari; Gorodin, Svetlana; Glater, Elizabeth E; Hochman, Ayala; Melamed, Eldad

doi:10.1016/s0197-0186(96)00150-7

Cited by 85 publications

(42 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The concept of using DOPA, quinones, and other melanin precursors or precursor derivatives to inhibit or kill leukemia cells and other diseased cells is not novel (4,8,10,15,18,22,31,33,34,36,38). Although much testing remains, the in vitro effectiveness and selectivity of 3-AT suggests that it may serve as a novel chemotherapeutic agent against myeloid leukemias.…”

Section: Discussionmentioning

confidence: 99%

Selective cytotoxicity of 3-amino-l-tyrosine correlates with peroxidase activity

Bruno

Herman

Cano

et al. 1999

In Vitro Cell.Dev.Biol.-Animal

View full text Add to dashboard Cite

In the presence of 3-amino-L-tyrosine (3-AT), abundant brown pigment forms in human HL-60 cells, but not in a variety of other cell lines, which are reported to be lower in mean myeloperoxidase (MPO) content than HL-60. Cells were assessed for peroxidase activity with an ABTS-based colorimetric assay and compared to values obtained with known amounts of human myeloperoxidase. HL-60 cells were estimated to contain the equivalent of 37.1 ng myeloperoxidase/10(6) cells versus 26.1 and 5.0 ng/10(6) cells for human K562 and murine RAW 264.7 cell lines, respectively. HL-60 cells exhibited a nearly 60% inhibition of proliferation and > 70% reduction in cell viability after 4 d of culture in the presence of 100 microg 3-AT per ml. Higher concentrations of 3-AT (up to 400 microg/ml) for 4 d reduced HL-60 proliferation by 80% and decreased viability to 1-3%. Comparable levels of cytotoxicity were achieved in KG-1 cells after 7 d with 200 or 400 microg 3-AT per ml. K562 cells exhibited a 40% reduction in cell number after 7 d with 400 microg 3-AT per ml, but concentrations less than 400 microg/ml did not significantly affect K562 proliferation. K562 viability remained unchanged with doses of 3-AT up to 400 microg/ml. RAW 264.7 cells exhibited unchanged viability and proliferation in the presence of 3-AT at concentrations up to 400 microg 3-AT per ml. K562, KG-1, and RAW 264.7 cells exhibited no evidence of brown pigment formation in the presence of 3-AT and medium containing 10% fetal bovine serum. However, RAW 264.7 cells that were converted to protein-free medium and exposed to 3-AT exhibited intense brown pigment in some cell nuclei. A high percentage of HL-60 cells treated with 3-AT exhibited membrane blebbing, pyknosis, and nuclear fragmentation, which was not observed among other 3-AT-treated cell lines. A mechanism involving toxic intermediates of peroxidase-mediated "aminomelanin" formation is hypothesized.

show abstract

Section: Discussionmentioning

confidence: 99%

Selective cytotoxicity of 3-amino-l-tyrosine correlates with peroxidase activity

Bruno

Herman

Cano

et al. 1999

In Vitro Cell.Dev.Biol.-Animal

View full text Add to dashboard Cite

show abstract

“…Dopamine and L-dopa have been reported to be neurotoxic (2,3) and to induce apoptosis (4)(5)(6), but the underlying molecular mechanism is unclear. The inhibition of dopa-dependent apoptosis by antioxidants supports the potential link between oxidative stress and apoptosis (2,(7)(8)(9)(10)(11). One possible source of free radicals may involve the one-electron reduction of 0-quinones formed during oxidation of dopamine (12,13).…”

Section: Introductionmentioning

confidence: 65%

The possible role of one-electron reduction of aminochrome in the neurodegenerative process of the dopaminergic system

2001

View full text Add to dashboard Cite

We present for discussion a possible molecular mechanism explaining the formation of reactive oxygen species involved in the neurodegenerative process of dopaminergic system in Parkinson's disease. This new hypothesis involves one-electron reduction of aminochrome to o-semiquinone radical, which seems to be the reaction responsible for neurodegenerative process of dopaminergic system. Leukoaminochrome o-semiquinone is extremely reactive with oxygen, which reoxidizes by reducing oxygen to superoxide radicals. Superoxide radicals enzymatically or spontaneously dismutate to dioxygen and hydrogen peroxide which is a precursor of hydroxyl radicals. ESR-experiments have showed that aminochrome o-semiquinone is extremely reactive in the presence of oxygen compared to dopamine o-semiquinone. In addition, the antioxidant enzymes superoxide dismutase and catalase play a prooxidant role by increasing the autoxidation rate and formation of superoxide radicals. One electron reduction of aminochrome to o-semiquinone can be performed by flavoenzymes which use NADPH and NADH as electron donator. The ability of aminochrome o-semiquinone to autoxidize in the presence of oxygen gives rise to a redox cycling process which will continue until oxygen, NADH and/or NADPH are depleted. Depletion of NADPH will prevent glutathione reductase from reducing glutathione, which is one of the main antioxidants in the cell. In addition depletion of NADH will prevent the formation of ATP in the electron transport chain in the mitochondria. Two antioxidants, probably, neuroprotective reactions are also discussed.

show abstract

“…The types of kynurenine pathway pigments range from the xanthomattins, a form that predominates in the eye and thought to be involved in cataract formation (Vazquez et al, 2000) to the melanin family of pigments (Vogliardi et al,2004), to the antibiotic, cinnabarinic acid (Vazquez et al, 2000). As a general class, the toxicity of pigment molecules and their reactive precursors has been well recognized, including the well-known kernicterus induced by bilirubin pigment and the toxicity of neuromelanin when it is not adequately sequestered (Offen et al, 1997). In-vitro, the type of melanin formed can be strongly affected by the presence of the kynurenine metabolite 3-hydroxyanthranilic acid (Figure 1), which shifts the production of the classic polymerized black eumelanin to the formation of a reddish-brown pigment that is less-completely polymerized and potentially more soluble (Soddu et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Two complex genotypes relevant to the kynurenine pathway and melanotropin function show association with schizophrenia and bipolar disorder

Miller

Murakami

Ruczinski

et al. 2009

Schizophrenia Research

View full text Add to dashboard Cite

Prior studies of mRNA expression, protein expression, and pathway metabolite levels have implicated dysregulation of the kynurenine pathway in the etiology of schizophrenia and bipolar disorder. Here we investigate whether genes involved in kynurenine pathway regulation might interact with genes that respond to kynurenine metabolites, to enhance risk for these psychiatric phenotypes. Candidate genes were selected from prior studies of genetic association, gene expression profiling and animal models. [GC] conferred an OR maximal for schizophrenia alone (4.84, p= 0.005), carried by 8% of schizophrenia cases. The combined risk posed by these related, complex genotypes is greater than any identified single locus and may derive from co-regulation of the kynurenine pathway by interacting genes, a lack of adequate melantropin-controlled sequestration of the kynurenine-derived pigments, or the production of melanotropin receptor ligands through kynurenine metabolism.

show abstract

Dopamine–melanin induces apoptosis in PC12 cells; possible implications for the etiology of Parkinson's disease

Cited by 85 publications

References 31 publications

Selective cytotoxicity of 3-amino-l-tyrosine correlates with peroxidase activity

Selective cytotoxicity of 3-amino-l-tyrosine correlates with peroxidase activity

The possible role of one-electron reduction of aminochrome in the neurodegenerative process of the dopaminergic system

Two complex genotypes relevant to the kynurenine pathway and melanotropin function show association with schizophrenia and bipolar disorder

Contact Info

Product

Resources

About