Transport at the Blood-Brain Barrier

The blood-brain barrier (BBB) is a selective barrier formed by endothelial cells that hne the cerebral microvessels and is present in all vertebrate animals [ 1], It consists of a network of capillaries in the human brain with an approximately total length of 600 km and an average distance of 40 pm from each capillary [2]. 

The BBB serves two important functions. First, it protects the brain from xenobiotics, and second, it maintains an ideal environment for the brain [15]. 

In addition to the blood-brain barrier, two other barrier layers limit and regulate molecular exchange at the interface between the blood and the neural tissue and its fiuid spaces the choroid plexus epithelium between blood and ventricular CSF and the arachnoid epithelium between blood and subarachnoid CSF. These CNS barriers perform a number of functions such as the ionic homeostasis, the restriction of small molecule permeation, the specific transport of small molecules required to enter or leave the brain, the restriction and regulation of large molecule traffic by reducing the fluid-phase endocytosis via pinocytotic vesicles, the separation of peripheral and central neurotransmitter pools, and the immune privilege [16]. 

The extracellular space ofthe brain can be divided into two major compartments, the CSF and the interstitial fluid (ISF). The CSF and the ISF are separated from the blood by the choroid plexus or the BCS FB and the brain capillary or BBB, respectively. No anatomical barrier exists between the CSF and the ISF a functional barrier is built up by the flow of CSF from its formation site (choroid plexus) to its absorption site (arachnoid villi) [15]. In the case of a human brain, 20 ml CSF is produced per hour and the complete turnover ofthe total 100 ml CS F occurs approximately within 4—5 h, whereas only 2 ml ISF is renewed per hour compared to the total amount of 300 ml ISF [17, 18]. Neurons are bathed by the extracellular (or interstitial) fluid of the brain (ECF = ISF) that forms the microenvironment ofthe CNS [19]. ISF and CSF are low-protein fluids (plasma CSF ratio 260) due to the tightness of the CNS barrier layers [20] furthermore, the brain has no true lymph or lymphatics. 

Both the BBB and the BCSFB actively regulate the type and concentration of molecules transported to and from the extracellular fluid, CSF, and intracellular fluid [21]. Because of its large surface area ( 20ni /1.3 kg brain) and the short diffusion distance between neurons and capillaries (8-20 pm), the endothelium plays a predominant role in regulating the brain environment [1]. The BCSFB also contributes to this process besides playing other roles [22]. It was proposed 

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Drug-Carrier Transporters at the Blood-Brain Barrier... 

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McAllister MS, Krizanac-Bengez L, Macchia F, Naftalin RJ, Pedley KC, Mayberg MR, Marroni M, Leaman S, Stanness KA, Janigro D (2001) Mechanisms of glucose transport at the blood brain barrier an in vitro study. Brain Res 904 20-30. 

THE ROLE OF DRUG TRANSPORTERS AT THE BLOOD-BRAIN BARRIER A.G. de Boer, I.C.J. van derSandt, P.J. Gaillard - 629-656... 

Figure 10.4 Scheme of proposed localization of important drug transporters at the blood-brain barrier. Adapted from Miecz et al. [121], Dallas et al. [184], and Miller [198]. 

Table 10.1 Suggested exogenous substrates for MCT transport at the blood-brain barrier.

Miller, D.S. (2005) The future of efflux transporters at the blood-brain barrier lessons from the periphery, in Efflux Transporters and the Blood-Brain Barrier (ed. E.M. Taylor), Nova Science Publishers, Inc., New York. 

Graff, C. L., Pollack, G. M. (2004). Drug transport at the blood-brain barrier and the choroid plexus. Current Drug Metabolism, 5(1), 95-108. 

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Fig. 2.1 Glucose and ketone body transporters with hypoxia. The relative increase in moncar-boxylate (MCTl) and glucose (GLUTl) transporters at the blood—brain barrier following 10% (0.5 atm. oxygen) exposure of hypobaric-hypoxia. Quantification of cerebral capillary density, as measured by GLUTl immunostaining, and MCTl immunoreactivities (number of counts per mm ) showed about a 30% upregulation of MCT 1 and GLUTl transporters with 3 week hypoxic exposure in rat brain. P < 0.05, hypoxic vs. normoxic...

Kakee, A., Terasaki, T., Sugiyama, Y., 1996. Brain efflux index as a novel method of analyzing efflnx transport at the blood-brain barrier. The Journal of Pharmacology and Experimental Therapeutics, 271(3), pp. 1550-1559. 

Morimoto K, Nakakariya M, Shirasaka Y, Kakinuma C, Fujita T, Tamai I, Ogihara T (2008) Oseltamvir (Tamiflu) efflux transport at the blood-brain barrier via P-glycoprotein. Drug Metab Dispos 36 6-9. 

Kinetic studies of glucose transport at the blood-brain barrier (Daniel et al, 1978 Cremer ei al, 1979) have shown that transport capacity is significantly lower in the suckling rat compared to the mature animal. Because of this limited capacity, the activity of the hexose transport system in neonates may be relatively easily depressed by acute exposure to high levels of lead. 

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