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Long-term retention of β-carbolines in brain neuromelanin
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Vise andre og tillknytning
2004 (engelsk)Inngår i: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 111, nr 2, s. 141-157Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

beta-Carbolines show structural resemblance to the neurotoxic N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and are metabolized to mitochondrial toxicants. Humans are continuously exposed to low levels of beta-carbolines through cooked food, coffee, alcoholic beverages and tobacco smoke. beta-Carbolines have previously been detected in higher levels in the pigmented substantia nigra than in the cortex of humans. The distribution of 3H-labelled harman and norharman in the brain of pigmented and albino mice and in frogs (a species having neuromelanin) was studied by tape-section and light-microscopic autoradiography. Furthermore, the binding of these beta-carbolines to dopamine-melanin and melanin granules from Sepia officinalis was examined. The results revealed a high affinity binding to melanin and a long-term retention (up to 30 days) in pigmented tissues, including neuromelanin-containing neurons of frogs after a single injection. The role of long-term exposure to food-related beta-carbolines and a retention of these compounds in pigment-containing neurons in the induction of idiopathic Parkinson's disease should be further considered.

sted, utgiver, år, opplag, sider
2004. Vol. 111, nr 2, s. 141-157
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-93503DOI: 10.1007/s00702-003-0080-0PubMedID: 14767717OAI: oai:DiVA.org:uu-93503DiVA, id: diva2:166997
Tilgjengelig fra: 2005-09-23 Laget: 2005-09-23 Sist oppdatert: 2017-12-14bibliografisk kontrollert
Inngår i avhandling
1. Selective Retention of β-Carbolines and 7,12-Dimethylbenz[a]anthracene in the Brain: Role of Neuromelanin and Cytochrome P450 for Toxicity
Åpne denne publikasjonen i ny fane eller vindu >>Selective Retention of β-Carbolines and 7,12-Dimethylbenz[a]anthracene in the Brain: Role of Neuromelanin and Cytochrome P450 for Toxicity
2005 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2005. s. 61
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 17
Emneord
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
HSV kategori
Forskningsprogram
toxikologi
Identifikatorer
urn:nbn:se:uu:diva-5941 (URN)91-554-6347-9 (ISBN)
Disputas
2005-10-14, C4:301, BMC, Husargatan 3, Uppsala, 09:30
Opponent
Veileder
Tilgjengelig fra: 2005-09-23 Laget: 2005-09-23 Sist oppdatert: 2018-01-13bibliografisk kontrollert

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