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Review
. 2022 Aug 18;14(8):1729.
doi: 10.3390/pharmaceutics14081729.

In Vitro Models of the Blood-Cerebrospinal Fluid Barrier and Their Applications in the Development and Research of (Neuro)Pharmaceuticals

Fatemeh Dabbagh  1 , Horst Schroten  1 , Christian Schwerk  1
Affiliations
Review

In Vitro Models of the Blood-Cerebrospinal Fluid Barrier and Their Applications in the Development and Research of (Neuro)Pharmaceuticals

Fatemeh Dabbagh et al. Pharmaceutics. .

Abstract

The pharmaceutical research sector has been facing the challenge of neurotherapeutics development and its inherited high-risk and high-failure-rate nature for decades. This hurdle is partly attributable to the presence of brain barriers, considered both as obstacles and opportunities for the entry of drug substances. The blood-cerebrospinal fluid (CSF) barrier (BCSFB), an under-studied brain barrier site compared to the blood-brain barrier (BBB), can be considered a potential therapeutic target to improve the delivery of CNS therapeutics and provide brain protection measures. Therefore, leveraging robust and authentic in vitro models of the BCSFB can diminish the time and effort spent on unproductive or redundant development activities by a preliminary assessment of the desired physiochemical behavior of an agent toward this barrier. To this end, the current review summarizes the efforts and progresses made to this research area with a notable focus on the attribution of these models and applied techniques to the pharmaceutical sector and the development of neuropharmacological therapeutics and diagnostics. A survey of available in vitro models, with their advantages and limitations and cell lines in hand will be provided, followed by highlighting the potential applications of such models in the (neuro)therapeutics discovery and development pipelines.

Keywords: BCSFB; blood–cerebrospinal fluid barrier; choroid plexus; drug permeability; drugs; in vitro model; therapeutics.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of anatomical location, physiological properties, and pharmacologically related transport systems of the BCSFB. (A) The BCSFB structure is comprised of the choroid plexus polarized cuboidal epithelial cells surrounding the highly permeable fenestrated capillaries of stromal core and tight junctional strands uniting adjacent epithelial cells. The innermost capillary (containing red blood cells), with leaky inter-endothelial gap junctions, is alongside the underlying stroma/basement membrane extracellular matrix. The epithelial basolateral surface faces stroma/blood and is in contact with interstitial fluid (ISF). The brush border apical membrane containing microvilli faces the adjacent CSF. (B) The main transport-relevant features of the BCSFB in terms of influx and efflux transport systems responsible for supplying nutrients, hormones, and therapeutics to the brain/CSF or acting to eliminate metabolites, xenobiotics, and neurotoxic compounds, respectively, are depicted.
Figure 2
Figure 2
Various possible in vitro BCSFB model platforms are schematically depicted here. (A) Static bicameral devices or alternatively known as cell culture filter inserts monolayers. This compartmentalized model, as the mostly utilized configuration by a preponderance of studies, represents culture of choroid plexus epithelial cells either in standard or inverted format on a suitable permeable filter insert; (B) Co-culture and multi-culture filter inserts. Here, choroid plexus epithelial cells are grown on porous cell culture inserts alongside endothelial, mesenchymal (e.g., pericytes), and/or glial cells either cultivated into the bottom of a multi-well plate in which the insert is located (non-contact) or seeded on the opposite side of the inserts containing epithelial cells (leading to a so-called back-to-back contact co-culture); (C) Three-dimensional cultures and organoids; (D) Dynamic cultures or microfluidic devices. The upper and lower channels of the devices are separated to model the luminal and abluminal membrane interfaces based on cell culture direction and a tunable shear stress is induced by a continuous flow of culture medium.
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Grants and funding

This work was supported by funding from the German Federal Ministry of Education and Research, BMBF (FKZ: 16GW0325 (BrainAim)). For the APC we acknowledge financial support by Deutsche Forschungsgemeinschaft within the funding programme “Open Access Publikationskosten” as well as by Heidelberg University.

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