Drug Development for Central Nervous System Diseases Using In vitro Blood-brain Barrier Models and Drug Repositioning

Abstract

An important goal of biomedical research is to translate basic research findings into practical clinical implementation. Despite the advances in the technology used in drug discovery, the development of drugs for central nervous system diseases remains challenging. The failure rate for new drugs targeting important central nervous system diseases is high compared to most other areas of drug discovery. The main reason for the failure is the poor penetration efficacy across the blood-brain barrier. The blood-brain barrier represents the bottleneck in central nervous system drug development and is the most important factor limiting the future growth of neurotherapeutics. Meanwhile, drug repositioning has been becoming increasingly popular and it seems a promising field in central nervous system drug development. In vitro blood-brain barrier models with high predictability are expected for drug development and drug repositioning. In this review, the recent progress of in vitro BBB models and the drug repositioning for central nervous system diseases will be discussed.

Keywords: Blood-brain barrier; central nervous system disease; drug development; drug repositioning; neurotherapeutics; penetration efficacy..

Fig. (1)

Schematic overview of in vitro BBB models composed of brain endothelial cells, pericytes, and astrocytes. Consider the important role of astrocytes and pericytes on the induction of BBB properties, several groups reported the triple culture model. Endothelial cells are grown in the presence of both astrocytes and pericytes. In the case of the construction of BBB model using the insert membrane, brain endothelial cells are seeded onto the upper surface of the insert membrane while pericytes grow on the opposite surface of the membrane, and astrocytes are placed at the bottom of the well. In contrast to the static environment in standard culture conditions, blood vessels are exposed to shear stress in vivo. Based on this aspect, several flow-based BBB models, including the triple culture model, have been reported. To make a spheroid or organoid BBB model, mixed cells consist of endothelial cells, astrocytes, and pericytes are cultured in the same well and led to make 3D organized BBB models. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

Schematic diagram of PAMPA model. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (3)

Features of cell culture inserts and calculation of permeability. Commercially available cell-culture inserts have been used most widely to construct in vitro BBB models. A researcher has to choose from cell culture inserts from different pore diameters, pore densities, and membrane material according to the research purpose. Bar in the representative image of Transwell indicates 5 μm. In general, the Permeability of the substrate is calculated by apparent permeability (Papp) or transendothelial permeability coefficient (Pe). (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (4)

Schematic overview of application of in vitro BBB model. Cell-culture based BBB model is widely accepted as a powerful tool to evaluate the BBB physiology, pathophysiology, pharmacology, and drug development. The BBB acts as a biological device that maintains brain homeostasis due to selective uptake and restriction of substances that enter the central nervous system from the blood. Their special features are achieved by the interaction among components of the neurovascular unit. In vitro BBB model has been provided numerous insights about these complex mechanisms of development and maintenance of the BBB. Since BBB plays a critical role in the protection of the brain against harmful substances from peripheral fluids, disruption of the BBB evokes brain edema formation and allows the penetration of toxic substances and inflammatory cells, and leads to neuronal damage. In vitro BBB model is a powerful tool to evaluate the mechanism of BBB disruption under these pathophysiological conditions and search a BBB protective drug to prevent the development of CNS disease. The BBB is a key player to protect the brain, on the other hand, it acts as major barrier that is difficult to overcome for the development of CNS drugs. Several potential routes for permeation across the BBB are known, such as passive diffusion, ABC transporter efflux, carrier-mediated influx, receptor-mediated transcytosis, and adsorptive-mediated transcytosis. The prediction of effective drug penetration across the BBB using an in vitro BBB model is important for the development of centrally acting drugs. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (5)

Publications indexed in PubMed based on keyword ‘drug repositioning’. More than 2300 publications have been indexed based on the keywords drug repositioning since 2013 and that number is increasing year on year.

Fig. (6)

(A, B) A comparison of traditional drug discovery and development for central nervous system diseases versus drug repositioning using in vitro Blood-Brain Barrier (BBB) model.. The attempts to develop new treatments for CNS diseases have costly and disappointing results, and require a long period of time and high expenditure, whereas the repurposing of safe existing market drugs provides a cost-effective and time-saving alternative.