Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-7429
Authors: Schulze, Sarina
Reinhardt, Sven
Freese, Christian
Schmitt, Ulrich
Endres, Kristina
Title: Identification of trichlormethiazide as a Mdr1a/b gene expression enhancer via a dual secretion-based promoter assay
Online publication date: 15-Jul-2022
Language: english
Abstract: Transporters of the ATP-binding cassette (ABC) family such as MDR1 play a pivotal role in persistence of brain homeostasis by contributing to the strict permeability properties of the blood-brain barrier. This barrier on one hand compromises treatment of central nervous system diseases by restricting access of drugs; on the other hand, an impaired or altered function of barrier building cells has been described in neurological disorders. The latter might contribute to increased vulnerability of the brain under pathological conditions or even enforce pathogenesis. Here, we present a novel approach for a systematic examination of drug impact on Mdr1 gene expression by establishing a dual reporter gene assay for the murine upstream core promoters of Mdr1a and b. We validated the time-resolved assay in comparison with single reporter gene constructs and applied it to analyze effects of a Food and Drug Administration (FDA)-approved drug library consisting of 627 substances. The chemo-preventive synthetic dithiolethione oltipraz was reidentified with our assay as an already known inducer of Mdr1 gene expression. Together with two newly characterized modifiers - gemcitabine and trichlormethiazide - we prove our findings in a blood-brain barrier culture model as well as in wild-type and Mdr1 knockout mice. In sum, we could demonstrate that our dual reporter gene assay delivers results, which also persist in the living animal and consequently is applicable for further analysis and prediction of Mdr1 regulation in vivo.
DDC: 610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 04 Medizin
FB 09 Chemie, Pharmazie u. Geowissensch.
Place: Mainz
ROR: https://ror.org/023b0x485
DOI: http://doi.org/10.25358/openscience-7429
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY-NC-ND
Information on rights of use: https://creativecommons.org/licenses/by-nc-nd/3.0/
Journal: Pharmacology research & perspectives
3
1
Pages or article number: e00109
Publisher: Wiley
Publisher place: Chichester
Issue date: 2015
ISSN: 2052-1707
Publisher URL: http://dx.doi.org/10.1002/prp2.109
Publisher DOI: 10.1002/prp2.109
Appears in collections:DFG-OA-Publizieren (2012 - 2017)

Files in This Item:
  File Description SizeFormat
Thumbnail
identification_of_trichlormet-20220713090351432.pdf549.31 kBAdobe PDFView/Open