In Vitro Models of CNS Barriers
This chapter reviews the history and modern applications of isolated preparations of the three main CNS barrier layers and cell culture preparations derived from them. In vitro models give valuable mechanistic information but also provide useful assay sys
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In Vitro Models of CNS Barriers N. Joan Abbott, Diana E.M. Dolman, Siti R. Yusof, and Andreas Reichel
Abstract This chapter reviews the history and modern applications of isolated preparations of the three main CNS barrier layers and cell culture preparations derived from them. In vitro models give valuable mechanistic information but also provide useful assay systems for drug discovery and delivery programmes. However, it is important to take into account practical issues including species differences and the degree to which the differentiated state of the in vivo barrier is retained. The range of models available is reviewed, with a critical evaluation of their strengths and weaknesses, and guidance in selecting and optimizing a suitable model for particular applications. New understanding of the unstirred water layers and paracellular leak pathway in in vitro preparations gives greater insights into the “intrinsic permeability” of the membrane, and a variety of techniques permit characterization of the transport systems and enzymes contributing to barrier function. Increasingly, aspects of CNS pathology are being modelled in cell culture, aiding the optimization of drug delivery regimes in pathological conditions.
N.J. Abbott (*) • D.E.M. Dolman BBB Group, Institute of Pharmaceutical Science, King’s College London, Franklin Wilkins Building 3.10, 150 Stamford St, London, SE1 9NH, UK e-mail: [email protected] S.R. Yusof HICoE Centre for Drug Research, Universiti Sains Malaysia, Minden, Penang 11800, Malaysia A. Reichel Bayer Pharma AG, Global Drug Discovery, DMPK, Berlin D-13353, Germany
M. Hammarlund-Udenaes et al. (eds.), Drug Delivery to the Brain, AAPS Advances in the Pharmaceutical Sciences Series 10, DOI 10.1007/978-1-4614-9105-7_6, © American Association of Pharmaceutical Scientists 2014
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Introduction
From the earliest demonstration of restricted exchange between the blood and the brain (Ehrlich 1885) leading to the modern understanding of the blood–CNS barriers, animal experiments and clinical observations have provided valuable information about the physiology and pathology of the barrier layers. However, obtaining mechanistic information from such studies at the cellular and molecular level is complex and time-consuming, and it is often difficult to obtain sufficient spatial and temporal resolution. The situation was dramatically improved by the introduction of in vitro methods (reviewed in Joó 1992).
6.1.1
Background and Early History
The first successful isolation of cerebral microvessels (Siakotos and Rouser 1969; Joó and Karnushina 1973) prepared the way for development of in vitro models of the blood–brain barrier (BBB), which have contributed to current understanding of its physiology, pharmacology and pathophysiology (reviewed in Joó 1992). Methods have also been developed for in vitro models of the choroid plexus and of the arachnoid epithelium (blood–CSF barrier, BCSFB). However, this proliferation of in vitro models and techniques causes problems
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