Blood brain barrier development

Wolburg, H., and A. Lippoldt. 2002. Tight junctions of the blood-brain barrier Development, composition and regulation. Vase Pharmacol 38 323. 

Schulze, C. and Firth, J. A., Interendothehal junctions during blood-brain barrier development in the rat morphological changes at the level of individual tight junctional contacts, Dev. Brain Res., 69, 85, 1992. 

Qin, Y. and Sato, T.N., Mouse multidrug resistance la/3 gene is the earliest known endothelial cell differentiation marker during blood-brain barrier development, Dev. Dyn., 202(2), 172, 1995. 

Mizee, M.R., Wooldrik, D., Lakeman, K.A.M., et ah, 2013. Retinoic acid induces blood-brain barrier development. J. Neurosci. 33, 1660-1671. 

Certain neutral technetium complexes can be used to image cerebral perfusion (Fig. 4). Those in Figure 4a and 4b have been approved for clinical use. Two other complexes (Fig. 4c and 4d) were tested in early clinical trials, but were not developed further. An effective cerebral perfusion agent must first cross the blood brain barrier and then be retained for the period necessary for image acquisition. Tc-bicisate is retained owing to a stereospecific hydrolysis in brain tissue of one of the ester groups to form the anionic complex TcO(ECD) , which does not cross the barrier. This mechanism of retention is termed metaboHc trapping. 

The sedation side effect commonly observed on administration of classical antihistaminic drugs has been attributed in part to the ease with which many of these compounds cross the blood brain barrier. There have been developed recently a series of agoits, for example, terfenadine (198), which cause reduced sedation by virtue of decreased penetration into the CNS. This is achieved by making them more hydrophilic. Synthesis of a related compound, ebastine (197),... 

Liu X, Tu M, Kelly RS, Chen C and Smith BJ. Development of a computational approach to predict blood-brain barrier permeability. Drug Metab Dispos 2004 32 132-9. 

In parallel with the identification of distinct transporters for GABA there has been continued interest in the development of selective blockers of these transporters and the therapeutic potential that could result from prolonging the action of synaptically released GABA. It has been known for a long time that certain pro-drugs of nipecotic add (e.g. nipecotic acid ethyl ester) are able to cross the blood-brain barrier and are effective anticonvulsants in experimental models of epilepsy. More recently, several different systemically active lipophillic compounds have been described that act selectively on GAT-1, GAT-2 or GAT-3 (Fig. 11.4). Of these, tiagabine (gabitiil), a derivative of nipecotic acid that acts preferentially on GAT -1, has proved clinically useful in cases of refractory epilepsy. 

Endogenous estrogens are known to be active in a number of areas of the brain. There are indications that estrogens may play a role in mood, locomotor activity, pain sensitivity, vulnerability to neurodegenerative diseases and cognition (McEwan, 1999). In humans, the blood brain barrier is not fiilly developed at birth and, for this reason, the central nervous system (CNS) may be more sensitive to phytoestrogens in utero or at birth. As ERs are expressed in the CNS, phytoestrogens may also be active in this area. 

With disruption of this barrier, molecules such as albumin freely enter the brain and ions and water follow. Because the brain lacks a well-developed lymphatic system, clearance of plasma constituents is slow, edema occurs, and intracranial pressure rises. At lower levels of exposure, subtle dysfunction of the blood-brain barrier may contribute to neurobehavioral deficits in children (Bressler and Goldstein 1991 Goldstein 1993). The particular vulnerability of the fetus and infant to the neurotoxicity of lead may be due in part to immaturity of the blood-brain barrier and to the lack of the high-affinity leadbinding protein in astroglia, which is discussed later in this section. Results of measurements of transendothelial electrical resistance across the blood-brain barrier from mice of various ages showed that lead potentiates cytokines-induced increase in ion permeability of the blood-brain barrier (Dyatlov et al. 

Moorhouse SR, Carden S, Drewitt PN, et al. 1988. The effect of chronic low level lead exposure on blood-brain barrier function in the developing rat. Biochem Pharmacol 37 4539-4547. 

Cecchelli, R, Berezowski, V, Lundquist, S, Culot, M, Renftel, M, Dehouck, MP, and Fenart, L, 2007. Modelling of the blood-brain barrier in drug discovery and development. Nat Rev Drug Discov 6, 650-661. 

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