Nerbio Sistema Zentrala

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307

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

aaa

22

16

3133

32

1930

29 1823

26

2728

25

20

24

14

15

89

11

12

710

Brain, lateral viewA

Brain, frontal sectionB

Brain

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311

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

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22

23

24

25

aaa

11

9

75

3

1615

22

2018

17

21

8

414

13

26

24

23

29

25

16

2022

17

15

2

19

2

6

12

10

27

28

30

19

1821

Cerebrum, medial viewA

Base of brainB

Brain

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81

viernes 3 de diciembre de 2010

Garun odoleztatzea

81

viernes 3 de diciembre de 2010

Garun odoleztatzeaEnrike G. Argandoña

Neurozientzia kliniko eta esperimentaleko laborategia (LaNCE)

Euskal Herriko Unibertsitatea

http://www.ehu.es/LaNCE

Iruñea. Uztaila 2006

81

viernes 3 de diciembre de 2010

http://www.ehu.es/LaNCE

Garun odoleztatzea

82

viernes 3 de diciembre de 2010

Garun odoleztatzea

Arteria-sistema aferentea

82

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Garun odoleztatzea

Arteria-sistema aferentea

Bena-sistema eferentea

82

viernes 3 de diciembre de 2010

83

Garun odoleztatzea

viernes 3 de diciembre de 2010

Pisuaren %2

83

Garun odoleztatzea

viernes 3 de diciembre de 2010

Pisuaren %2

Garun bolumenaren %1

83

Garun odoleztatzea

viernes 3 de diciembre de 2010

Pisuaren %2

Garun bolumenaren %1

Bihotz gastuaren %20

83

Garun odoleztatzea

viernes 3 de diciembre de 2010

Pisuaren %2

Garun bolumenaren %1

Bihotz gastuaren %20

Energiaren %65

83

Garun odoleztatzea

viernes 3 de diciembre de 2010

85

Garun odoleztatzeaBabes mekanismoak

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Zirkulazio sistemikoaren kontrola

85

Garun odoleztatzeaBabes mekanismoak

viernes 3 de diciembre de 2010

Zirkulazio sistemikoaren kontrola

Garun-odol basoen autorregulazioa

85

Garun odoleztatzeaBabes mekanismoak

viernes 3 de diciembre de 2010

Zirkulazio sistemikoaren kontrola

Garun-odol basoen autorregulazioa

Fluxuaren banaketa

85

Garun odoleztatzeaBabes mekanismoak

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96

Garun odoleztatzea

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96

Garun odoleztatzea

viernes 3 de diciembre de 2010

97

viernes 3 de diciembre de 2010

97

viernes 3 de diciembre de 2010

97

viernes 3 de diciembre de 2010

Barrera hematoentzefalikoa

116

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Barrera hematoentzefalikoa

116

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Barrera hematoentzefalikoa

116

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Barrera hematoentzefalikoa117

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Tipos de transporte

viernes 3 de diciembre de 2010

!

Paracellular aqueouspathway

Transcellularlipophilicpathway

Transport proteins Receptor-mediatedtranscytosis

Adsorptivetranscytosis

a b c d e

Water-solubleagents

Lipid-solubleagents

Glucose,amino acids,nucleosides

Vinca alkaloids,Cyclosporin A,AZT

Insulin,transferrin

Albumin, otherplasma proteins

+

++++

+ ++

++++

+ ++– – – –

––

+

++++

+ ++––––

++++

+ ++

––

+

Astrocyte Astrocyte

Brain

Blood

Endothelium

Tightjunction

Adherens junctionA cell–cell junction also known as zonula adherens, which is characterized by the intracellular insertion of microfilaments. If intermediate filaments are inserted in lieu of microfilaments, the resulting junction is referred to as a desmosome.

Perivascular endfeetThe specialized foot-processes of perivascular astrocytes that are closely apposed to the outer surface of brain microvessels, and have specialized functions in inducing and regulating the BBB.

PericyteA cell of mesodermal origin, and contractile-phagocytic phenotype, associated with the outer surface of capillaries.

The brain endothelial transporters that supply the brain with nutrients include the GLUT1 glucose carrier, several amino acid carriers (including LAT1, L-system for large neutral amino acids), and transporters for nucleosides, nucleobases and many other substances10. Several organic anion and cation transporters identified in other tissues and the choroid plexus are also prov-ing to be expressed on the brain endothelium. Where compounds need to be moved against a concentration gradient, the energy may come from ATP (as in the ABC family of transporters, including P-glycoprotein (Pgp) and multidrug resistance-related proteins, MRPs), or the Na+ gradient created by operation of the abluminal Na+,K+-ATPase. Some transporters (for example, GLUT1 and LAT1) are bidirectional, moving substrates down the concentration gradient, and can be present on both luminal and abluminal membranes, or predominantly on one. Quantification of GLUT1 expression on luminal and abluminal endothelial membranes is complicated by the fact that some antibodies do not recognize the trans-porter when the C-terminal is masked, as it may be in the luminal membrane23. Among the efflux transporters, Pgp is concentrated on the luminal membrane24, whereas the Na+-dependent transporters are generally abluminal,

specialized for moving solutes out of the brain25,26. They include several Na+-dependent glutamate transporters (excitatory amino acid transporters 1–3; EAAT1–3)27, which move glutamate out of the brain against the large opposing concentration gradient (<1 µM in ISF compared with ~100 µM in plasma) (FIG. 2). The clear apical–basal polarity of brain endothelial cells noted above is hence reflected in their polarized transport function20,28.

Induction of BBB propertiesWhat causes the endothelium of blood vessels growing into the brain during development to become so specialized? It has been clear from the earliest histological studies that brain capillaries are surrounded by or closely associated with several cell types, including the perivascular endfeet of astrocytic glia, pericytes, microglia and neuronal proc-esses (FIG. 2). In the larger vessels (arterioles, arteries and veins), smooth muscle forms a continuous layer, replacing pericytes1. Neuronal cell bodies are typically no more than ~10 µm from the nearest capillary6. These close cell–cell associations, particularly of astrocytes and brain capil-laries, led to the suggestion that they could mediate the induction of the specific features of the barrier phenotype in the capillary endothelium of the brain29.

Figure 3 | Pathways across the blood–brain barrier. A schematic diagram of the endothelial cells that form the blood–brain barrier (BBB) and their associations with the perivascular endfeet of astrocytes. The main routes for molecular traffic across the BBB are shown. a | Normally, the tight junctions severely restrict penetration of water-soluble compounds, including polar drugs. b | However, the large surface area of the lipid membranes of the endothelium offers an effective diffusive route for lipid-soluble agents. c | The endothelium contains transport proteins (carriers) for glucose, amino acids, purine bases, nucleosides, choline and other substances. Some transporters are energy-dependent (for example, P-glycoprotein) and act as efflux transporters. AZT, azidothymidine. d | Certain proteins, such as insulin and transferrin, are taken up by specific receptor-mediated endocytosis and transcytosis. e | Native plasma proteins such as albumin are poorly transported, but cationization can increase their uptake by adsorptive-mediated endocytosis and transcytosis. Drug delivery across the brain endothelium depends on making use of pathways b–e; most CNS drugs enter via route b. Modified, with permission, from REF. 8 ! (1996) Elsevier Science.

REVIEWS

44 | JANUARY 2006 | VOLUME 7 www.nature.com/reviews/neuro

Tipos de transporte

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Unidad neurogliovascular

119

accumulation of neuropeptides in the brain ISF. Uptake of mostcirculating peptides by the brain can be comparedwith uptake ofdrugs such as acetaminophen, which exerts analgesic activitywith an uptake of only 0.2%/g brain, or morphine, which hasan uptake of <0.02%/g.CaveolaeRaft-dependent endocytosis is cholesterol sensitive, clathrin in-dependent internalization of ligands and receptors from theplasma membrane (Lajoie and Nabi, 2007). It encompasses en-docytosis of caveolae, smooth plasmalemmal vesicles that formsubdomains of cholesterol and sphingolipid-rich rafts that areenriched in caveolin-1. The caveolae control transcellular per-meability by regulating endocytosis, transcytosis, and signalingin lipid-based microdomains of the BBB (Parton and Richards,2003). The caveolar membranes contain receptors for transfer-rin, insulin, albumin, ceruloplasmin, RAGE, LDL, HDL, interleu-kin-1, and vesicle-associated membrane protein-2 (Wolburg,2006) (Figure 3C). Signaling complexes at caveolin-1 includeheterotrimeric G proteins, members of the MAPK pathway, srctyrosine kinase, protein kinase C, and the endothelial NO syn-thase. The involvement of caveolin-1 in NO and calcium signalinghas been demonstrated in caveolin-1-deficient mice (Drab et al.,2001). VEGFR-2 (Labrecque et al., 2003) and P-gp (Jodoin et al.,2003) are also closely associated with caveolin-1. Caveolin-1can also influence the levels of TJ proteins in BEC (Song et al.,2007a). The role of caveolae in BBB functions in health and dis-ease remains to be explored.

Enzymatic BBBEndothelial cells of the BBB provide a metabolic barrier by ex-pressing a number of enzymes that modify endogenous and ex-ogenous molecules, which otherwise could bypass the physicalbarrier and negatively affect neuronal function (Pardridge, 2005).The capillary endothelium, pericytes, and astrocytes express

a variety of ectoenzymes on the plasma membranes, includingaminopeptidases, endopeptidases, cholinesterase, and others.

Passive Transport by the Brain FluidsBrain ISF-CSF ‘‘bulk flow’’ mediates transport of molecules intothe CSF at a slow rate, irrespective of their size (Davson, 1976;Zlokovic, 2005). The CSF acts as a sink for potentially toxicmolecules and metabolic waste products. Toxic molecules andmetabolic waste products are removed from the CSF backinto the circulation by active transport or facilitated diffusionacross the choroid plexus epithelium, or by vacuolar transportacross the epithelial arachnoid granulations.

Neurovascular UnitEndothelium, the site of anatomical BBB, neurons, and non-neuronal cells (e.g., pericytes, astrocytes, andmicroglia) togetherform a functional unit, often referred to as a neurovascular unit(Figure 4A) (Lo et al., 2003; Iadecola, 2004; Hawkins and Davis,2005; Zlokovic, 2005). The close proximity of different nonneuro-nal cell typeswith eachother andwith neurons allows for effectiveparacrine regulations that are critical for normal CNS functioninganddiseaseprocesses (Boillee et al., 2006a;DeaneandZlokovic,2007; Lok et al., 2007). These include regulation of hemodynamicneurovascular coupling, microvascular permeability, matrix in-teractions, neurotransmitter inactivation, neurotrophic coupling,and angiogenic and neurogenic coupling (Figure 4B).Vascular versus Neuronal Origin of Brain DisordersBrain disorders may have a vascular origin (Figure 4A, arrow 1).Vascular cells, i.e., endothelium and pericytes, can directly affectneuronal and synaptic functions through changes in the bloodflow, the BBB permeability, nutrient supply, faulty clearance oftoxicmolecules, failure of enzymatic functions, the altered secre-tion of trophic factors and matrix molecules, abnormal expres-sion of vascular receptors, or induction of ectoenzymes.

Figure 4. Schematic of the Neurovascular Unit(A) Endothelial cells and pericytes are separated by the basement membrane. Pericyte processes sheathe most of the outer side of the basement membrane. Atpoints of contact, pericytes communicate directly with endothelial cells through the synapse-like peg-socket contacts. Astrocytic endfoot processes unsheathethe microvessel wall, which is made up of endothelial cells and pericytes. Resting microglia have a ‘‘ramified’’ shape. In cases of neuronal disorders that havea primary vascular origin, circulating neurotoxinsmay cross the BBB to reach their neuronal targets, or proinflammatory signals from the vascular cells or reducedcapillary blood flow may disrupt normal synaptic transmission and trigger neuronal injury (arrow 1). Microglia recruited from the blood or within the brain and thevessel wall can sense signals from neurons (arrow 2). Activated endothelium, microglia, and astrocytes signal back to neurons, which in most cases aggravatesthe neuronal injury (arrow 3). In the case of a primary neuronal disorder, signals from neurons are sent to the vascular cells and microglia (arrow 2), which activatethe vasculo-glial unit and contributes to the progression of the disease (arrow 3).(B) Coordinated regulation of normal neurovascular functions depends on the vascular cells (endothelium and pericytes), neurons, and astrocytes.

Neuron 57, January 24, 2008 ª2008 Elsevier Inc. 185

Neuron

Review

viernes 3 de diciembre de 2010

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