Acute Effects of Short-chain Alkylglycerols on Blood-brain Barrier Properties of Cultured Brain Endothelial Cells

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2013 Apr 27

PMID 23617601

Citations 16

Authors

P Hulper

S Veszelka

F R Walter

H Wolburg

P Fallier-Becker

J Piontek

I E Blasig

M Lakomek

W Kugler

M A Deli

Affiliations

Soon will be listed here.

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 vitro 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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References

Deli M . Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery. Biochim Biophys Acta. 2008; 1788(4):892-910. DOI: 10.1016/j.bbamem.2008.09.016. View

Bruewer M, Hopkins A, Hobert M, Nusrat A, Madara J . RhoA, Rac1, and Cdc42 exert distinct effects on epithelial barrier via selective structural and biochemical modulation of junctional proteins and F-actin. Am J Physiol Cell Physiol. 2004; 287(2):C327-35. DOI: 10.1152/ajpcell.00087.2004. View

Furuse M, Sasaki H, Fujimoto K, Tsukita S . A single gene product, claudin-1 or -2, reconstitutes tight junction strands and recruits occludin in fibroblasts. J Cell Biol. 1998; 143(2):391-401. PMC: 2132845. DOI: 10.1083/jcb.143.2.391. View

Blasig I, Winkler L, Lassowski B, Mueller S, Zuleger N, Krause E . On the self-association potential of transmembrane tight junction proteins. Cell Mol Life Sci. 2006; 63(4):505-14. PMC: 11136374. DOI: 10.1007/s00018-005-5472-x. View

Erdlenbruch B, Jendrossek V, Eibl H, Lakomek M . Transient and controllable opening of the blood-brain barrier to cytostatic and antibiotic agents by alkylglycerols in rats. Exp Brain Res. 2001; 135(3):417-22. DOI: 10.1007/s002210000553. View

Dodelet-Devillers A, Cayrol R, van Horssen J, Haqqani A, de Vries H, Engelhardt B . Functions of lipid raft membrane microdomains at the blood-brain barrier. J Mol Med (Berl). 2009; 87(8):765-74. DOI: 10.1007/s00109-009-0488-6. View

van Vliet E, Zibell G, Pekcec A, Schlichtiger J, Edelbroek P, Holtman L . COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats. Neuropharmacology. 2009; 58(2):404-12. DOI: 10.1016/j.neuropharm.2009.09.012. View

Dhanikula R, Argaw A, Bouchard J, Hildgen P . Methotrexate loaded polyether-copolyester dendrimers for the treatment of gliomas: enhanced efficacy and intratumoral transport capability. Mol Pharm. 2008; 5(1):105-16. DOI: 10.1021/mp700086j. View

Farkas A, Szatmari E, Orbok A, Wilhelm I, Wejksza K, Nagyoszi P . Hyperosmotic mannitol induces Src kinase-dependent phosphorylation of beta-catenin in cerebral endothelial cells. J Neurosci Res. 2005; 80(6):855-61. DOI: 10.1002/jnr.20521. View

10.

Kemper E, Boogerd W, Thuis I, Beijnen J, van Tellingen O . Modulation of the blood-brain barrier in oncology: therapeutic opportunities for the treatment of brain tumours?. Cancer Treat Rev. 2004; 30(5):415-23. DOI: 10.1016/j.ctrv.2004.04.001. View

11.

Krause G, Winkler L, Piehl C, Blasig I, Piontek J, Muller S . Structure and function of extracellular claudin domains. Ann N Y Acad Sci. 2009; 1165:34-43. DOI: 10.1111/j.1749-6632.2009.04057.x. View

12.

Dejana E, Orsenigo F, Lampugnani M . The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci. 2008; 121(Pt 13):2115-22. DOI: 10.1242/jcs.017897. View

13.

Erdlenbruch B, Alipour M, Fricker G, Miller D, Kugler W, Eibl H . Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries. Br J Pharmacol. 2003; 140(7):1201-10. PMC: 1574140. DOI: 10.1038/sj.bjp.0705554. View

14.

Veszelka S, Pasztoi M, Farkas A, Krizbai I, Ngo T, Niwa M . Pentosan polysulfate protects brain endothelial cells against bacterial lipopolysaccharide-induced damages. Neurochem Int. 2006; 50(1):219-28. DOI: 10.1016/j.neuint.2006.08.006. View

15.

Erdlenbruch B, Kugler W, Schinkhof C, Neurath H, Eibl H, Lakomek M . Blood-brain barrier opening with alkylglycerols: Biodistribution of 1-O-pentylglycerol after intravenous and intracarotid administration in rats. J Drug Target. 2005; 13(3):143-50. DOI: 10.1080/10611860400029085. View

16.

Piontek J, Fritzsche S, Cording J, Richter S, Hartwig J, Walter M . Elucidating the principles of the molecular organization of heteropolymeric tight junction strands. Cell Mol Life Sci. 2011; 68(23):3903-18. PMC: 4336547. DOI: 10.1007/s00018-011-0680-z. View

17.

Reardon D, Rich J, Friedman H, Bigner D . Recent advances in the treatment of malignant astrocytoma. J Clin Oncol. 2006; 24(8):1253-65. DOI: 10.1200/JCO.2005.04.5302. View

18.

Erdlenbruch B, Schinkhof C, Kugler W, Heinemann D, Herms J, Eibl H . Intracarotid administration of short-chain alkylglycerols for increased delivery of methotrexate to the rat brain. Br J Pharmacol. 2003; 139(4):685-94. PMC: 1573898. DOI: 10.1038/sj.bjp.0705302. View

19.

Abbott N, Ronnback L, Hansson E . Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2005; 7(1):41-53. DOI: 10.1038/nrn1824. View

20.

Perriere N, Demeuse P, Garcia E, Regina A, Debray M, Andreux J . Puromycin-based purification of rat brain capillary endothelial cell cultures. Effect on the expression of blood-brain barrier-specific properties. J Neurochem. 2005; 93(2):279-89. DOI: 10.1111/j.1471-4159.2004.03020.x. View