The effects of tesmilifene, a chemopotentiating agent, on brain endothelial cells
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1
Hungarian Academy of Sciences, Group of Molecular Neurobiology, Institute of Biophysics, Biological Research Center, Hungary
Tesmilifene, a tamoxifen-related compound, has chemopotentiating and cytoprotective properties in experimental and clinical studies. Treatment with tesmilifene caused temporary central nervous system side-effects in patients indicating the opening of the blood-brain barrier. Previous studies from our laboratory have shown that tesmilifene increases the permeability of the blood-brain barrier in rats. The aim of the present study was to test the direct effects of tesmilifene on blood-brain barrier functions using a cell culture-based model. Primary rat brain endothelial and glial cells were co-cultured using Transwell inserts and treated with tesmilifene (1-400 µM). Barrier integrity was measured by transendothelial electrical resistance and permeability for markers fluorescein and albumin. Activity of P-glycoprotein and multidrug resistance protein-1 was tested in the presence of inhibitors and tesmilifene. DAF-FM diacetate was used as a fluorescent indicator of nitric oxide release. MTT and lactate dehydrogenase assays were used as toxicity tests. Short-term tesmilifene treatment decreased the transendothelial electrical resistance of endothelial monolayers, and increased the permeability for albumin. Tesmilifene did not change the functions of P-glycoprotein, but significantly decreased the activity of the multidrug resistance associated protein-1 and the production of vasoactive mediator nitric oxide. Long-term tesmilifene treatment dose-dependently reduced the viability of brain endothelial cells. Tesmilifene affected several blood-brain barrier functions, decreased the barrier integrity, inhibited the activity of the MRP-1 efflux pump, and caused toxic effects in concentrations exceeding the therapeutical level in brain endothelial cells. Our data indicate that tesmilifene increases the permeability of the blood-brain barrier by directly acting on brain endothelial cells and could be exploited to promote drug transport to brain.
Conference:
IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010.
Presentation Type:
Poster Presentation
Topic:
Homeostatic and neuroendocrine systems
Citation:
Walter
F,
Veszelka
S,
Ábrahám
C and
Deli
M
(2010). The effects of tesmilifene, a chemopotentiating agent, on brain endothelial cells.
Front. Neurosci.
Conference Abstract:
IBRO International Workshop 2010.
doi: 10.3389/conf.fnins.2010.10.00140
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Received:
29 Apr 2010;
Published Online:
29 Apr 2010.
*
Correspondence:
Fruzsina Walter, Hungarian Academy of Sciences, Group of Molecular Neurobiology, Institute of Biophysics, Biological Research Center, Szeged, Hungary, walter@brc.hu