Patented In Vitro Blood-Brain Barrier Models in CNS Drug Discovery

Abstract

The blood-brain barrier (BBB) is a regulatory interface between the circulation and the central nervous system (CNS). Therapy of neurological diseases is limited due to restricted penetration of pharmacons across the BBB. Models for screening the brain penetration of drug candidates are needed early in drug discovery. Culture-based models are useful tools for both basic research on BBB, and testing the permeability of new therapeutical molecules. This review focuses on patented in vitro BBB models and their potential application in CNS drug discovery. Cell culture models using primary and immortalized brain endothelial cells of non-human and human origin, in co-culture or mono-culture setting, in static or dynamic conditions are discussed, as well as methods to induce BBB properties in such in vitro models. The aim of these models is to reproduce as many aspects as possible of the in vivo BBB. All models should show some elements of general endothelial and specific BBB properties, like physiologically realistic cell architecture, restrictive paracellular pathway, and functional expression of transport mechanisms. Though no "ideal in vitro BBB model" has been constructed yet, the currently available models provide valuable information on BBB permeability and are useful tools in CNS drug discovery.

Generation of an Immortalized Murine Brain Microvascular Endothelial Cell Line as an <em>In Vitro</em> Blood Brain Barrier Model

“…GC treatment led to an increase in the expression of these proteins and to the rearrangement of VE-cadherin to the cytoskeleton. The direct GC-mediated regulation of tight junction proteins occludin and claudin-5 appears through GC response elements in their promoter regions 4,7,19 . Additionally, claudin-5 was identified as a novel estrogen target in vascular endothelium 10 …”

Repetitive acute intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus

“…BDNF induction following 3×wAIH is associated with TrkB up regulation, suggesting that repetitive AIH may represent a novel and effective means of endogenous BDNF delivery that avoids the difficulties attendant to protein delivery to the CNS (e.g. access across the blood brain barrier, receptor down-regulation, immune responses triggered by protein delivery; Banks and Erickson, 2010; Tóth et al, 2011). As such, repetitive AIH may be an effective treatment for certain forms of injury and/or disease (Mitchell, 2007), including spinal injury (Lovett-Barr et al, 2012).…”

A versatile lab-on-a-chip tool for modeling biological barriers

“…Culture-based BBB models greatly differ in complexity. Immortalized cell lines and mono-cultures of brain endothelial cells can be used as simplified BBB models [9][10][11], but the barrier properties of primary cell-based co-culture models are better [2,12,13]. We established a syngeneic rat BBB model based on the co-culture of primary brain endothelial cells with pericytes and glial cells mimicking the in vivo anatomical position of the cells.…”