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Dopamine melanin-loaded PC12 cells: A model for studies on pigmented neurons of substantia nigra
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neurofarmakologi, drogberoende och beteende)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Bioaktivering och toxicitet)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Bioaktivering och toxicitet)
2005 (English)In: Pigment Cell Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 18, no 4, 306-314 p.Article in journal (Refereed) Published
Abstract [en]

The most conspicuous feature in idiopathic parkinsonism is the degeneration of pigmented neurons in the substantia nigra. A major problem for the study of the significance of neuromelanin for the development of parkinsonism is that common experimental animals lack neuromelanin in substantia nigra. The aim of this study was to develop an in vitro model that could be used to study the role of neuromelanin in chemically induced toxicity in dopaminergic cells. Cultured neuron-like PC12 cells were exposed to synthetic dopamine melanin (0-1.0 mg/ml) for 48 h, resulting in uptake of dopamine melanin particles into the cells. The intracellular distribution of dopamine melanin granules was similar to that found in neuromelanin-containing neurons. Dopamine melanin, up to 0.5 mg/ml, had negligible effects on ultrastructure, induction of the endoplasmic reticulum-stress protein glucose regulating protein 78, activation of caspase-3 and cell viability. The decreased cell viability in response to the cytotoxic peptide amyloid-beta25-35 was similar in melanin-loaded cells and in control cells without melanin. The results of the studies suggest that melanin-loaded PC12 cells can serve as an in vitro model for studies on the role of neuromelanin for the toxicity of chemicals, in particular neurotoxicants with melanin affinity, in pigmented neurons.

Place, publisher, year, edition, pages
2005. Vol. 18, no 4, 306-314 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93505DOI: 10.1111/j.1600-0749.2005.00239.xPubMedID: 16029423OAI: oai:DiVA.org:uu-93505DiVA: diva2:166999
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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Brittebo, Eva B

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