Acute effects of short-chain alkylglycerols on blood-brain barrier properties of cultured brain endothelial cells

P. Hülper, S. Veszelka, F. R. Walter, H. Wolburg, P. Fallier-Becker, J. Piontek, I. E. Blasig, M. Lakomek, W. Kugler, M. Deli

Research output: Contribution to journalArticle

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Abstract

Background and Purpose The blood-brain barrier (BBB) restricts drug penetration to the brain preventing effective treatment of patients suffering from brain tumours. Intra-arterial injection of short-chain alkylglycerols (AGs) opens the BBB and increases delivery of molecules to rodent brain parenchyma in vivo. The mechanism underlying AG-mediated modification of BBB permeability is still unknown. Here, we have tested the effects of AGs on barrier properties of cultured brain microvascular endothelial cells. Experimental Approach The effects of two AGs, 1-O-pentylglycerol and 2-O-hexyldiglycerol were examined using an in vitroâ€...BBB model consisting of primary cultures of rat brain endothelial cells, co-cultured with rat cerebral glial cells. Integrity of the paracellular, tight junction-based, permeation route was analysed by functional assays, immunostaining for junctional proteins, freeze-fracture electron microscopy, and analysis of claudin-claudin trans-interactions. Key Results AG treatment (5 min) reversibly reduced transendothelial electrical resistance and increased BBB permeability for fluorescein accompanied by changes in cell morphology and immunostaining for claudin-5 and β-catenin. These short-term changes were not accompanied by alterations of inter-endothelial tight junction strand complexity or the trans-interaction of claudin-5. Conclusion and Implications AG-mediated increase in brain endothelial paracellular permeability was short, reversible and did not affect tight junction strand complexity. Redistribution of junctional proteins and alterations in the cell shape indicate the involvement of the cytoskeleton in the action of AGs. These data confirm the results from in vivo studies in rodents characterizing AGs as adjuvants that transiently open the BBB.

Original languageEnglish
Pages (from-to)1561-1573
Number of pages13
JournalBritish Journal of Pharmacology
Volume169
Issue number7
DOIs
Publication statusPublished - Aug 2013

Fingerprint

Blood-Brain Barrier
Endothelial Cells
Tight Junctions
Brain
Claudin-5
Permeability
Rodentia
Intra-Arterial Injections
Catenins
Cell Shape
Cytoskeleton
Fluorescein
Electric Impedance
Brain Neoplasms
Neuroglia
Electron Microscopy
Proteins
Therapeutics
Pharmaceutical Preparations

Keywords

  • blood-brain barrier
  • brain endothelial cells
  • claudin-5
  • electron microscopy
  • permeability
  • short-chain alkylglycerols
  • tight junctions
  • transendothelial electrical resistance

ASJC Scopus subject areas

  • Pharmacology

Cite this

Acute effects of short-chain alkylglycerols on blood-brain barrier properties of cultured brain endothelial cells. / Hülper, P.; Veszelka, S.; Walter, F. R.; Wolburg, H.; Fallier-Becker, P.; Piontek, J.; Blasig, I. E.; Lakomek, M.; Kugler, W.; Deli, M.

In: British Journal of Pharmacology, Vol. 169, No. 7, 08.2013, p. 1561-1573.

Research output: Contribution to journalArticle

Hülper, P, Veszelka, S, Walter, FR, Wolburg, H, Fallier-Becker, P, Piontek, J, Blasig, IE, Lakomek, M, Kugler, W & Deli, M 2013, 'Acute effects of short-chain alkylglycerols on blood-brain barrier properties of cultured brain endothelial cells', British Journal of Pharmacology, vol. 169, no. 7, pp. 1561-1573. https://doi.org/10.1111/bph.12218
Hülper, P. ; Veszelka, S. ; Walter, F. R. ; Wolburg, H. ; Fallier-Becker, P. ; Piontek, J. ; Blasig, I. E. ; Lakomek, M. ; Kugler, W. ; Deli, M. / Acute effects of short-chain alkylglycerols on blood-brain barrier properties of cultured brain endothelial cells. In: British Journal of Pharmacology. 2013 ; Vol. 169, No. 7. pp. 1561-1573.
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AU - Veszelka, S.

AU - Walter, F. R.

AU - Wolburg, H.

AU - Fallier-Becker, P.

AU - Piontek, J.

AU - Blasig, I. E.

AU - Lakomek, M.

AU - Kugler, W.

AU - Deli, M.

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AB - Background and Purpose The blood-brain barrier (BBB) restricts drug penetration to the brain preventing effective treatment of patients suffering from brain tumours. Intra-arterial injection of short-chain alkylglycerols (AGs) opens the BBB and increases delivery of molecules to rodent brain parenchyma in vivo. The mechanism underlying AG-mediated modification of BBB permeability is still unknown. Here, we have tested the effects of AGs on barrier properties of cultured brain microvascular endothelial cells. Experimental Approach The effects of two AGs, 1-O-pentylglycerol and 2-O-hexyldiglycerol were examined using an in vitroâ€...BBB model consisting of primary cultures of rat brain endothelial cells, co-cultured with rat cerebral glial cells. Integrity of the paracellular, tight junction-based, permeation route was analysed by functional assays, immunostaining for junctional proteins, freeze-fracture electron microscopy, and analysis of claudin-claudin trans-interactions. Key Results AG treatment (5 min) reversibly reduced transendothelial electrical resistance and increased BBB permeability for fluorescein accompanied by changes in cell morphology and immunostaining for claudin-5 and β-catenin. These short-term changes were not accompanied by alterations of inter-endothelial tight junction strand complexity or the trans-interaction of claudin-5. Conclusion and Implications AG-mediated increase in brain endothelial paracellular permeability was short, reversible and did not affect tight junction strand complexity. Redistribution of junctional proteins and alterations in the cell shape indicate the involvement of the cytoskeleton in the action of AGs. These data confirm the results from in vivo studies in rodents characterizing AGs as adjuvants that transiently open the BBB.

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