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01.07.2012

Effects of Chemotherapeutics on Organotypic Corticostriatal Slice Cultures Identified by A Panel of Fluorescent and Immunohistochemical Markers

verfasst von: Annette Nørregaard, Stine Skov Jensen, Jesper Kolenda, Charlotte Aaberg-Jessen, Karina Garnier Christensen, Poul Henning Jensen, Henrik Daa Schrøder, Bjarne Winther Kristensen

Erschienen in: Neurotoxicity Research | Ausgabe 1/2012

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Abstract

Effects of chemotherapeutics on glioma cell lines and spheroids are usually investigated without evaluating the effects of chemotherapeutics on normal brain tissue. To perform such investigations, the aim of this study was to establish a panel of markers for detection of general cell death and more specific neuronal and glial degeneration induced by chemotherapeutics in organotypic rat corticostriatal slice cultures. The slice cultures were exposed to the alkylating agents temozolomide (TMZ) and nimustine (ACNU), the tyrosine kinase inhibitor imatinib mesylate (IM) and the microtubule-destabilizing agent vincristine (VCR). Densitometric measurements of uptake of the fluorescent dye propidium iodide (PI) were used for quantifying cellular degeneration. Moreover, paraffin sections were hematoxylin eosine stained and immunostained for the neuronal marker microtubule-associated protein 2 (MAP2), the astroglial marker glial fibrillary acidic protein (GFAP), and the oligodendroglial marker p25α. The results showed that the supposed clinically relevant drug concentrations were non-toxic. However, a time dependent increase in PI uptake was observed for high drug concentrations, except for TMZ, where no toxicity was observed. Corresponding immunostaining showed loss of MAP2 and increased expression of GFAP and p25α for cultures exposed to 1,000 nM VCR. Cultures exposed to high concentrations of ACNU and IM disintegrated, leaving no tissue for histology. In conclusion, corticostriatal slice cultures and the established panel of markers represent an excellent tool for detecting toxicity induced by chemotherapeutics. Toxicity was not detected at clinical concentrations, but high concentrations with toxic effects were identified suggesting that some of the earlier identified anti-cancer effects are general cytotoxic effects and not specific anti-cancer effects.

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Titel: Effects of Chemotherapeutics on Organotypic Corticostriatal Slice Cultures Identified by A Panel of Fluorescent and Immunohistochemical Markers
verfasst von: Annette Nørregaard
Stine Skov Jensen
Jesper Kolenda
Charlotte Aaberg-Jessen
Karina Garnier Christensen
Poul Henning Jensen
Henrik Daa Schrøder
Bjarne Winther Kristensen
Publikationsdatum: 01.07.2012
Verlag: Springer-Verlag
Erschienen in: Neurotoxicity Research / Ausgabe 1/2012
Print ISSN: 1029-8428
Elektronische ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-011-9300-9

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