Characterization of a Primate Blood-Brain Barrier Co-Culture Model Prepared from Primary Brain Endothelial Cells, Pericytes and Astrocytes

Abstract

Culture models of the blood-brain barrier (BBB) are important research tools. Their role in the preclinical phase of drug development to estimate the permeability for potential neuropharmaceuticals is especially relevant. Since species differences in BBB transport systems exist, primate models are considered as predictive for drug transport to brain in humans. Based on our previous expertise we have developed and characterized a non-human primate co-culture BBB model using primary cultures of monkey brain endothelial cells, rat brain pericytes, and rat astrocytes. Monkey brain endothelial cells in the presence of both pericytes and astrocytes (EPA model) expressed enhanced barrier properties and increased levels of tight junction proteins occludin, claudin-5, and ZO-1. Co-culture conditions also elevated the expression of key BBB influx and efflux transporters, including glucose transporter-1, MFSD2A, ABCB1, and ABCG2. The correlation between the endothelial permeability coefficients of 10 well known drugs was higher (R2 = 0.8788) when the monkey and rat BBB culture models were compared than when the monkey culture model was compared to mouse in vivo data (R2 = 0.6619), hinting at transporter differences. The applicability of the new non-human primate model in drug discovery has been proven in several studies.

Interactions of Nanoscale Self-Assembled Peptide-Based Assemblies with Glioblastoma Cell Models and Spheroids

“…As seen, the permeation of the Rhodmaine-B-labeled nanoassemblies at 2 μM concentration resulted in a higher apparent permeability with P app of 4.6 × 10 –6 cm/s, while that of the nanoassemblies at 10 μM concentration showed an apparent permeability constant P app of 2.7 × 10 –6 cm/s across the BBB model. The values obtained are in the range seen for drugs such as cimetidine and digoxin, which have been studied using in vitro models of BBB . Similar results have been observed for fluorescently labeled silica nanoparticles which showed permeability of the nanoparticles through an in vitro cocultured BBB model .…”

“…The values obtained are in the range seen for drugs such as cimetidine and digoxin, which have been studied using in vitro models of BBB. 106 Similar results have been observed for fluorescently labeled silica nanoparticles which showed permeability of the nanoparticles through an in vitro cocultured BBB model. 107 However, one must keep in mind that the ideal size and shape of nanoassemblies may need to be altered, given that the in vivo BBB structural integrity may be different.…”

Construction and Functional Evaluation of a Three-Dimensional Blood–Brain Barrier Model Equipped With Human Induced Pluripotent Stem Cell-Derived Brain Microvascular Endothelial Cells

“…5a, b and Table II). These results suggest that P-gp (ABCB1) in hiPS-BMECs is only marginally functional even in 3D culture, since the values for quinidine in a monkey in vitro BBB model and the prediction for human BBB were reported to be approximately 1.7 and 13.4, respectively (38,39). In addition, lack of P-gp function has been reported in BMECs derived from other hiPS cell lines (40).…”

Usefulness of a humanized tricellular static transwell blood–brain barrier model as a microphysiological system for drug development applications. - A case study based on the benchmark evaluations of blood-brain barrier microphysiological system

“…Lucifer Yellow does not permeate BBB because of its hydrophilicity, while caffeine diffuses freely across BBB because of its lipophilicity. A lot of studies used these two compounds as references reflecting BBB tightness [ [27] , [28] , [29] , [30] ]. TEER is a quick marker of high junctional tightness.…”