Disease Influence on BBB Transport in Inflammatory Disorders
During diseases of the central nervous system (CNS), such as Alzheimer’s, Parkinson’s, epilepsy, stroke and multiple sclerosis (MS), the protective function of the blood–brain barrier (BBB) is significantly impaired. The inflammatory response that is freq
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Disease Influence on BBB Transport in Inflammatory Disorders Geert J. Schenk, Gijs Kooij, Arie Reijerkerk, and Helga de Vries
Abstract During diseases of the central nervous system (CNS), such as Alzheimer’s, Parkinson’s, epilepsy, stroke and multiple sclerosis (MS), the protective function of the blood–brain barrier (BBB) is significantly impaired. The inflammatory response that is frequently associated with such brain diseases may underlie the loss of the integrity and function of the BBB. Consequentially, the delivery and disposition of drugs to the brain will be altered and may influence the treatment efficiency of CNS diseases. Altered BBB transport of drugs into the CNS during diseases may be the result of changes in both specific transport and non-specific transport pathways. Potential alterations in transport routes like adsorptive-mediated endocytosis and receptor-mediated endocytosis may affect drug delivery to the brain. As such, drugs that normally are unable to traverse the BBB may reach their target in the diseased brain due to increased permeability. On the contrary, the delivery of (targeted) drugs could be hampered during inflammatory conditions due to disturbed transport mechanisms. Therefore, the inventory of the neuro-inflammatory status of the neurovasculature (or recovery thereof) is of utmost importance in choosing and designing an adequate drug targeting strategy under disease conditions. Within this chapter we discuss how the function of the BBB can be affected during disease and how this may influence the delivery of drugs into the diseased CNS.
G.J. Schenk, Ph.D. Department of Anatomy and Neurosciences, VU university medical center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands G. Kooij, Ph.D. • A. Reijerkerk, Ph.D. • H. de Vries, Ph.D. (*) Department of Molecular Cell Biology and Immunology, VU university medical center, Van der Boechorststraat 7, Amsterdam 1081 BT, The Netherlands e-mail: [email protected] 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_21, © American Association of Pharmaceutical Scientists 2014
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Introduction
The blood–brain barrier (BBB) is a complex cellular network consisting of brain endothelial cells lining the cerebral microvasculature which form a continuous cellular barrier between the central nervous system (CNS) and the bloodstream. The BBB plays a crucial role in maintaining brain homeostasis, which is necessary for the stability and activity of nerve cells (Abbott 2002; Abbott et al. 2006). The BBB is also the “firewall” that prevents the entry of toxic compounds and immune cells into the CNS (Quan 2006). The functionality of the BBB is achieved through the interactions of cells comprising the BBB: these include not only endothelial cells but also astrocytes, pericytes and neighbouring CNS cells (Hawkins and Davis 2005). A number of specific transport and enzyme systems are in place at the BBB which
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