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Norharman-induced motoric impairment in mice: Neurodegeneration and glial activation in substantia nigra
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Ulleråker, Akademiska sjukhuset.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. (Bioaktivering och toxicitet)
2006 (engelsk)Inngår i: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 113, nr 3, s. 313-329Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The beta-carboline norharman is present in cooked food and tobacco smoke and show structural resemblance to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. C57BL/6 mice were injected subcutaneously with norharman (3 and 10 mg/kg) twice per day for five consecutive days. Eighteen hours after the last dose an increased expression of glial fibrillary acidic protein and fluoro-jade staining were demonstrated whereas the number of tyrosine hydroxylase positive cells were unchanged in the substantia nigra. Two weeks after the last treatment a decreased motor activity was observed whereas cognitive functions remained intact. In cultured PC12 cells norharman treatment induced mitochondrial dysfunction and increased the number of caspase-3 and TUNEL-positive cells. The results demonstrate that norharman induced apoptosis in cultured cells as well as early neurodegeneration, glial activation and sustained motor deficits in mice and suggest that exposure to norharman may contribute to idiopathic Parkinson's disease.

sted, utgiver, år, opplag, sider
2006. Vol. 113, nr 3, s. 313-329
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-93504DOI: 10.1007/s00702-005-0334-0PubMedID: 16075188OAI: oai:DiVA.org:uu-93504DiVA, id: diva2:166998
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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