Tesmilifene modifies brain endothelial functions and opens the blood-brain/blood-glioma barrier

Fruzsina R. Walter, S. Veszelka, Mária Pásztõi, Zoltán A. Péterfi, András Tõth, G. Rákhely, L. Cervenák, C. Ábrahám, M. Deli

Research output: Article

15 Citations (Scopus)

Abstract

Tesmilifene, a tamoxifen analog with antihistamine action, has chemopotentiating properties in experimental and clinical cancer studies. In our previous works, tesmilifene increased the permeability of the blood-brain barrier (BBB) in animal and culture models. Our aim was to investigate the effects of tesmilifene on brain microvessel permeability in the rat RG2 glioma model and to reveal its mode of action in brain endothelial cells. Tesmilifene significantly increased fluorescein extravasation in the glioma. Short-term treatment with tesmilifene reduced the resistance and increased the permeability for marker molecules in a rat triple co-culture BBB model. Tesmilifene also affected the barrier integrity in brain endothelial cells co-cultured with RG2 glioblastoma cells. Tesmilifene inhibited the activity of P-glycoprotein and multidrug resistance-associated protein-1 efflux pumps and down-regulated the mRNA expression of tight junction proteins, efflux pumps, solute carriers, and metabolic enzymes important for BBB functions. Among the possible signaling pathways that regulate BBB permeability, tesmilifene activated the early nuclear translocation of NFκB. The MAPK/ERK and PI3K/Akt kinase pathways were also involved. We demonstrate for the first time that tesmilifene increases permeability marker molecule extravasation in glioma and inhibits efflux pump activity in brain endothelial cells, which may have therapeutic relevance. Tesmilifene, a chemopotentiator in experimental and clinical cancer studies increases vascular permeability in RG2 glioma in rats and permeability for marker molecules in a culture model of the blood-brain barrier. Tesmilifene inhibits the activity of efflux pumps and down-regulates the mRNA expression of tight junction proteins, transporters, and metabolic enzymes important for the blood-brain barrier functions, which may have therapeutic relevance. Tesmilifene, a chemopotentiator in experimental and clinical cancer studies increases vascular permeability in RG2 glioma in rats and permeability for marker molecules in a culture model of the blood-brain barrier. Tesmilifene inhibits the activity of efflux pumps and down-regulates the mRNA expression of tight junction proteins, transporters, and metabolic enzymes important for the blood-brain barrier functions, which may have therapeutic relevance.

Original languageEnglish
Pages (from-to)1040-1054
Number of pages15
JournalJournal of Neurochemistry
Volume134
Issue number6
DOIs
Publication statusPublished - szept. 1 2015

Fingerprint

Blood-Brain Barrier
Glioma
Brain
Blood
Permeability
Tight Junction Proteins
Pumps
Rats
Endothelial cells
Molecules
Endothelial Cells
Capillary Permeability
tesmilifene
Messenger RNA
Enzymes
Down-Regulation
Neoplasms
Histamine Antagonists
P-Glycoprotein
Tamoxifen

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Tesmilifene modifies brain endothelial functions and opens the blood-brain/blood-glioma barrier. / Walter, Fruzsina R.; Veszelka, S.; Pásztõi, Mária; Péterfi, Zoltán A.; Tõth, András; Rákhely, G.; Cervenák, L.; Ábrahám, C.; Deli, M.

In: Journal of Neurochemistry, Vol. 134, No. 6, 01.09.2015, p. 1040-1054.

Research output: Article

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AU - Tõth, András

AU - Rákhely, G.

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