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Differential effects of dopamine melanin on norharman-induced toxicity in PC12 cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Eva Brittebo)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Eva Brittebo)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Eva Brittebo)
2007 (English)In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 114, no 7, 909-918 p.Article in journal (Refereed) Published
Abstract [en]

The food contaminant norharman structurally resembles MPTP a compound that selectively damages pigmented brain areas. Both compounds are sequestered and retained in melanin-containing neurons. The aim of the study was to examine whether intracellular melanin can modulate the toxicity of norharman in melanin-loaded PC12 cells. Dopamine melanin protected against norharman-induced upregulation of grp78, activation of caspase 3 and necrosis at low concentrations (5 and 50 µM). In contrast, at a high conentration (500 µM) there was a significantly increased expression of grp78, hsp90 and caspase and a disassociation of melanin aggregates and dispersal of melanin granules to swollen neurite terminals. In human populations, a long-term low-level exposure to toxicants with a high affinity to melanin will probably result in accumulation in melanin-containing neurons in vivo. Our data suggest that accumulation of a neurotoxicant in melanin-loaded cells may lead to increased cell stress, apoptotic signaling and disassociation of melanin aggregates.

Place, publisher, year, edition, pages
2007. Vol. 114, no 7, 909-918 p.
Keyword [en]
apoptosis, b-carboline, caspase 3, dopamine melanin, grp78, hsp90, neuromelanin, norharman, pigment
National Category
Pharmacology and Toxicology
Research subject
Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-93506DOI: 10.1007/s00702-006-0622-3ISI: 000248001800006OAI: oai:DiVA.org:uu-93506DiVA: diva2:167000
Available from: 2005-09-23 Created: 2005-09-23 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Selective Retention of β-Carbolines and 7,12-Dimethylbenz[a]anthracene in the Brain: Role of Neuromelanin and Cytochrome P450 for Toxicity
Open this publication in new window or tab >>Selective Retention of β-Carbolines and 7,12-Dimethylbenz[a]anthracene in the Brain: Role of Neuromelanin and Cytochrome P450 for Toxicity
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The ß-carbolines norharman and harman structurally resemble the synthetic compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that is known for its ability to damage neuromelanin-containing dopaminergic neurons of the substantia nigra and thereby induce parkinsonism. MPTP is, however, not normally present in the environment whereas the ß-carbolines are present in cooked food and tobacco smoke.

In this thesis it was demonstrated that norharman and harman had affinity to melanin and were retained in neuromelanin-containing neurons of frogs up to 30 days post-injection (the longest survival time examined). It was also demonstrated that norharman induced neurodegeneration, activation of glia cells and motor impairment in mice. Furthermore, this compound induced ER stress and cell death in PC12 cells. An in vitro model of dopamine melanin-loaded PC12 cells was developed in order to study the effect of melanin on norharman-induced toxicity. In this model, melanin seemed to attenuate toxicity induced by low concentrations of norharman. After exposure to the highest concentration of norharman, melanin clusters were disaggregated and there was an increased expression of stress proteins and caspases-3, known to be involved in apoptosis.

The polycyclic aromatic hydrocarbon, 7,12-dimethylbenz[a]anthracene was demonstrated to have a CYP1A1-dependent localization in endothelial cells in the choroid plexus, in the veins in the leptomeninges and in the cerebral veins of mice pre-treated with CYP1-inducers.

These results demonstrate that the distribution of environmental compounds could be influenced by the presence of neuromelanin and expression of CYP enzymes in the brain and that norharman may induce neurotoxic effects in vivo and in vitro.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 17
Keyword
Toxicology, β-carboline, neuromelanin, norharman, harman, parkinsonism, Parkinson's disease, motoric impairment, behaviour, glia cells, substantia nigra, dopamine melanin, PC12 cells, ER stress, grp78, hsp90, cytochrome P450, CYP1A1, CYP1B1, blood-brain interfaces, 7,12-dimethylbenz[a]anthracene, polycyclic aromatic hydrocarbon, endothelial cell, smooth muscle cell, bioactivation, Toxikologi
National Category
Pharmacology and Toxicology
Research subject
Toxicology
Identifiers
urn:nbn:se:uu:diva-5941 (URN)91-554-6347-9 (ISBN)
Public defence
2005-10-14, C4:301, BMC, Husargatan 3, Uppsala, 09:30
Opponent
Supervisors
Available from: 2005-09-23 Created: 2005-09-23Bibliographically approved

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