Astrocyte Blood-brain barrier

Blood-brain barrier A physicochemical barrier formed by astrocytes and capillary endothelial cells. It prevents toxic chemicals from entering CNS neurons from the systemic blood circulation. 

Fig. 15.2 Diagram showing a transverse cross-section of a cerebral capillary. The endothelial cells, responsible for the main barrier properties of the blood-brain barrier are separated from the astrocyte foot processes, pericytes and occasional neurons by the basement membrane. All these components make up the blood-brain barrier.

Fig. 15.3 D iagram showing a longitudinal cross-section of the blood-brain barrier, with the brain capillary endothelial cells sealed by the tight junctions and surrounded by pericytes and astrocyte foot processes. These cellular components of the BBB are separated by a basement membrane.

Basic Concepts Underlying the Pharmacogenomics of the Blood-Brain Barrier 317 15.1.2.3 Astrocytes in the Blood-Brain Barrier... 

Janzer RC, Raff MC. Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 1987 325 253-257. 

Constituents of the Blood-Brain Barrier 313 Endothelial Cells in the Blood-Brain Barrier 313 Pericytes in the Blood-Brain Barrier 315 Astrocytes in the Blood-Brain Barrier 317 Basement Membrane at the Blood-Brain Barrier 317 The Main Gene and Protein Targets for Pharmacogenomics of the Blood-Brain Barrier 319... 

Transferrin is an iron carrier protein that acts as a trophic survival factor for neurons, astrocytes and OLs. As the blood-brain barrier becomes established during development, neural cells become dependent on transferrin produced by OLs and choroid plexus epithelial cells (Fig. 25-14). OLs are the major source of transferrin in the CNS. This suggests an important function for OLs in... 

The blood-brain barrier is markedly different from peripheral capillaries Peripheral capillaries are fenestrated with openings up to 50 nm wide. In contrast, cerebral endothelial cells are closely connected by tight junctions and zonulae occludentes, resulting in extremely high transendothelial resistances of up to 1500-2000 12 cm2 [16] (Figure 17.1). The capillaries are surrounded by a basal membrane enclosing intermittently pericytes, which have been postulated to be involved in host defense. The outer surface of the basement membrane is covered by astrocytic foot processes. Most likely, secretion of soluble growth factors by astrocytes plays an important role in endothelial cell differentiation. 

Considering the spatial geometry of cerebral capillaries and capillary blood flow, a number of dynamic models of the blood-brain barrier have been developed, in which endothelial cells are cultured inside a permeable tube, the outer surface of which is coated with astrocytes. Supply of the cells with nutrients and artificial blood flow are maintained by using a peristaltic pump system [112, 113]. 

Ghazanfari FA, Stewart RR (2001) Characteristics of endothehal cells derived from the blood-brain barrier and of astrocytes in culture. Brain Res 890 49-65... 

Figure 14.15 A diagram to illustrate how the end-feet of an astrocyte are in direct contact with capillaries and with neurones. It is Likely that the endfeet of the astrocytes will extent over most of the surface of the capillaries, since they provide one component of the blood-brain barrier.

Brain microvascular EC monolayers together with an astrocyte-enriched subendothelial collagen gel can be used to simulate the blood-brain barrier (BBB) (39). Such systems are invaluable to screen for compounds able to penetrate the BBB to access brain tumors or metastases. In addition, glioma cell invasion into brain fragments has enabled better understanding of the properties of these highly invasive tumors and identification of potential therapeutic targets (40). 

Figure 3.9 The blood-brain barrier (BBB) is a major impediment to the delivery of drugs to the brain. In the brain, in order for a drug molecule to leave a capillary and snccessfnlly jonmey to a neuronal receptor, it must traverse multiple barriers. The walls of capillaries in the brain are different from those in non-brain tissnes. Tight junctions prevent the drugs from readily crossing the capillary. Next, in the brain, another type of cell, called an astrocyte, forms an additional barrier that must be traversed. Astrocytes are not present outside of the brain.

MPTP is also metabolized by other routes involving cytochromes P-450, FAD-dependent monooxygenases, and aldehyde oxidase. However, these seem to be detoxication pathways, as they divert MPTP away from uptake and metabolism in the brain. However, MPTP may inhibit its own metabolism by cytochromes P-450 and thereby reduce one means of detoxication. This example illustrates the importance of structure and physicochemical properties in toxicology. MPTP is sufficiently lipophilic to cross the blood-brain barrier and gain access to the astrocytes. The structure of the metabolite is important for uptake via the dopamine system, hence localizing the compound to a particular type of neuron. Again, uptake into mitochondria is presumably a function of structure, as a specific energy-dependent carrier is involved. 

MPTP is a molecule, which is sufficiently lipophilic to cross the blood-brain barrier and enter the astrocyte cells. Once in these cells, it can be metabolized by monoamine oxidase B to MPDP and then MPP both of which are charged molecules. These metabolites are therefore not able to diffuse out of the astrocyte into the bloodstream and away from the brain. However, the structure of MPP allows it to be taken up by a carrier system and concentrated in dopaminergic neurones. In the neurone, it inhibits the mitochondrial electron transport chain leading to damage to the neurone. 

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