In vitro blood–brain barrier permeability predictions for GABAA receptor modulating piperine analogs

Abstract

The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters.

Capsaicin and Piperine as Functional Excipients for Improved Drug Delivery across Nasal Epithelial Models

“…The effect by piperine on FD4 permeation across the RPMI 2650 cell layers did not increase with an increase in piperine concentration over the concentration range investigated (10-50 µM). It was previously proposed that piperine led to polarized paracellular opening of the blood-brain barrier [20] and increased drug absorption by fluidizing the brush border membrane while increasing microvilli length [21]. Furthermore, TEER measurements during the current permeation studies indicated a 8.99, 8.57, and 18.69 % decrease in the presence of 10, 25, and 50 µM piperine, respectively.…”

Assessment of HBEC-5i endothelial cell line cultivated in astrocyte conditioned medium as a human blood-brain barrier model for ABC drug transport studies

“…This parameter completely determines the interaction between the drugs and ABC transporter function (Food and drug administration, 2012;Hubatsch et al, 2007;Kikuchi et al, 2013). To date, only few studies on human BBB cell lines have evaluated this parameter (Eigenmann et al, 2016a;Jähne et al, 2016;Ma et al, 2014). In our model, ER parameter was higher in HBEC-5i with the HA conditioned medium than HBEC-5i alone.…”

Modélisationin vitrode la barrière hémato-encéphalique

“…Cependant le premier modèle fondé sur la co-culture de cellules endothéliales progénitrices circulantes en présence d'astrocytes, développé par Boyer-Di Ponio et al [39], présente des niveaux de perméabilité paracellulaire qui sont similaires à ceux de la lignée hCMEC/D3, et donc trop élevés pour étudier les mécanismes de transport/passage de petites molécules au travers de la BHE. En revanche, le modèle développé par Cecchelli et al [12] s'est avéré pertinent pour prédire la distribution cérébrale de petites molécules [12,41] mais aussi pour étudier les capacités de vectorisation de peptides [42], les utiles comme outils de criblage de molécules à destinée cérébrale. Leur utilisation a ainsi permis de réaliser des avancées significatives pour le traitement de la sclérose en plaques et de certaines tumeurs [21,45].…”