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Status: Bibliographieeintrag

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Verfasst von:Neuhaus, Winfried [VerfasserIn]   i
 Mahringer, Anne [VerfasserIn]   i
Titel:Reversible opening of the blood-brain barrier by claudin-5-binding variants of Clostridium perfringens enterotoxin's claudin-binding domain
Verf.angabe:Winfried Neuhaus, Anna Piontek, Jonas Protze, Miriam Eichner, Anne Mahringer, Eva-Anne Subileau, In-Fah M. Lee, Jörg D. Schulzke, Gerd Krause, Jörg Piontek
E-Jahr:2018
Jahr:2 February 2018
Umfang:15 S.
Fussnoten:Gesehen am 19.02.2020
Titel Quelle:Enthalten in: Biomaterials
Ort Quelle:Amsterdam [u.a.] : Elsevier Science, 1980
Jahr Quelle:2018
Band/Heft Quelle:161(2018), Seite 129-143
ISSN Quelle:0142-9612
Abstract:The blood-brain barrier (BBB) prevents entry of neurotoxic substances but also that of drugs into the brain. Here, the paracellular barrier is formed by tight junctions (TJs) with claudin-5 (Cldn5) being the main sealing constituent. Transient BBB opening by targeting Cldn5 could improve paracellular drug delivery. The non-toxic C-terminal domain of Clostridium perfringens enterotoxin (cCPE) binds to a subset of claudins, e.g., Cldn3, -4. Structure-based mutagenesis was used to generate Cldn5-binding variants (cCPE-Y306W/S313H and cCPE-N218Q/Y306W/S313H). These cCPE-variants were tested for transient TJ opening using multiple in vitro BBB models: Primary porcine brain endothelial cells, coculture of primary rat brain endothelial cells with astrocytes and mouse cerebEND cells. cCPE-Y306W/S313H and cCPE-N218Q/Y306W/S313H but neither cCPE-wt nor cCPE-Y306A/L315A (not binding to claudins) decreased transendothelial electrical resistance in a concentration-dependent and reversible manner. Furthermore, permeability of carboxyfluorescein (with size of CNS drugs) was increased. cCPE-Y306W/S313H but neither cCPE-wt nor cCPE-Y306A/L315A bound to Cldn5-expressing brain endothelial cells. However, freeze-fracture EM showed that cCPE-Y306W/S313H did not cause drastic TJ breakdown. In sum, Cldn5-binding cCPE-variants enabled mild and transient opening of brain endothelial TJs. Using reliable in vitro BBB models, the results demonstrate that cCPE-based biologics designed to bind Cldn5 improve paracellular drug delivery across the BBB.
DOI:doi:10.1016/j.biomaterials.2018.01.028
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext: https://doi.org/10.1016/j.biomaterials.2018.01.028
 Volltext: http://www.sciencedirect.com/science/article/pii/S0142961218300425
 DOI: https://doi.org/10.1016/j.biomaterials.2018.01.028
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:Blood brain barrier
 Claudin
 enterotoxin
 Paracellular drug delivery
 Tight junction
K10plus-PPN:169038638X
Verknüpfungen:→ Zeitschrift

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