Garun odoleztatzea

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Garun odoleztatzea
Enrike G. Argandoña
Neurozientzia kliniko eta esperimentaleko laborategia (LaNCE)
Euskal Herriko Unibertsitatea
http://www.ehu.es/LaNCE
Iruñea. Uztaila 2006

Garun odoleztatzea

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Garun odoleztatzea

Arteria-sistema aferentea

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Garun odoleztatzea

Arteria-sistema aferentea
Bena-sistema eferentea

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Garun odoleztatzea

Garun bolumenaren %1

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Garun odoleztatzea

Bihotz gastuaren %20

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Garun odoleztatzea

Bihotz gastuaren %20
Energiaren %65

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Garun odoleztatzea
Babes mekanismoak

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Garun odoleztatzea
Babes mekanismoak

Zirkulazio sistemikoaren kontrola

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Garun odoleztatzea
Babes mekanismoak

Garun-odol basoen autorregulazioa

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Garun odoleztatzea
Babes mekanismoak

Garun-odol basoen autorregulazioa
Fluxuaren banaketa

Garun barneko odol hodiak

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Arteriolak (50-100 µm)

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Arteriola terminalak (10-100µm)

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Benulak (± 30 µm)

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Benulak (± 30 µm)
Kapilareak (<30 µm)

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Garun odoleztatzea

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Garun odoleztatzea

Sare kapilarea

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Garun odoleztatzea

Sare kapilarea
Barrera hematoentzefalikoa

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Garun odoleztatzea

Sare kapilarea
Egitura-mekanismoak

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Garun odoleztatzea

Sare kapilarea
Egitura-mekanismoak
Mekanismo metabolikoak

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Garraio motak
a b c d e
Paracellular aqueous Transcellular Transport proteins Receptor-mediated Adsorptive
pathway lipophilic transcytosis transcytosis
pathway
Water-soluble Lipid-soluble Glucose, Vinca alkaloids, Insulin, Albumin, other
agents agents amino acids, Cyclosporin A, transferrin plasma proteins
nucleosides AZT
+++
+ +
+++
Blood –––– +
–+ + –
+ +
–+ + –
+
Tight
junction
–+ + + –
+ +
–+ + + –

– –
Endothelium – –
+++
Brain + +
+++

Astrocyte Astrocyte

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

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Zelulak

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REVIEWS

Basal lamina
Neuron
Interneuron

Tight
junction Astrocyte
Tight junction Pericyte Capillary
Zelulak

A belt-like region of adhesion Astrocyte
Endothelial
between adjacent cells. Tight
cell
junctions regulate paracellular
flux, and contribute to the b LIF
maintenance of cell polarity by
stopping molecules from a Tight
diffusing within the plane of the TGFβ
junction
membrane.
Tight ? bFGF
GLUT1
Abluminal membrane junction
Capillary
The endothelial cell membrane ANG1
that faces away from the vessel
Capillary Endothelial
lumen, towards the brain. Microglia LAT1
cell
Meninges
Endothelial Pgp GDNF
cell
The complex arrangement of
EAAT1–3 Astrocyte
three protective membranes
surrounding the brain, with a Basal
thick outer connective tissue lamina
layer (dura) overlying the ET1 TIE2 P2Y2 5-HT
barrier layer (arachnoid), and
finally the thin layer covering Figure 2 | Cellular constituents of the blood–brain barrier. The barrier is formed by capillary endothelial cells,
the glia limitans (pia). The sub- surrounded by basal lamina and astrocytic perivascular endfeet. Astrocytes provide the cellular link to the neurons.
arachnoid layer has a sponge-

at the BBB is observed in starvation and hypoxia53,54.
Zelularteko seinaleak BHEn
Blood Ligand Tight
junction
Receptor

↑Ca2+ ↑Ca2+
Endothelial cell
Pericyte
Smooth muscle

Basal Microglia
lamina

Neuron Astrocyte Neuron

Figure 5 | Complex cell–cell signalling at the blood–brain barrier. A portion of a
brain capillary wall, showing the main cell types present with the potential to signal to
each other. Pericytes are enclosed within the endothelial basal lamina and form the

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Garun endotelioa

Mitokondria ugari

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Garun endotelioa

Mitokondria ugari
Pinozitosiaren gabezia

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Garun endotelioa

Mitokondria ugari
Pinozitosiaren gabezia
Fenestrazioen gabezia

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Astroglia

BHEren indukzioa

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Astroglia

BHEren indukzioa
BHEren
mantenimendua

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Astroglia

BHEren indukzioa
BHEren
mantenimendua
Tonu baskularraren
kontrola

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Astroglia

BHEren indukzioa
BHEren
mantenimendua
Tonu baskularraren
kontrola
BHEren egitura?

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Perizitoak

Nortasun iluna
Pluripotentzialak
Parte hartzea
angiogenesian eta
BHEren ontzean

Apical membrane

Cingulin, JACOP, PAR3/6,
CASK, 7H6, Itch, MUPP1, Claudin 3, 5, 12
MAGI-1–3, ZONAB ZO-2 Occludin
AF6, RGS5 Tight
junction
JAMs,
ZO-3 ESAM
ZO-1
Basolateral
membrane

PECAM
α-, β-, γ-Catenin,
Desmoplakin, Adherens
p120ctn, ZO-1 junction
Actin/vinculin-based VE-cadherin
cytoskeleton

Basal lamina
Figure 4 | Molecular composition of endothelial tight junctions. Simplified and

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Iragazkortasun mikrobaskularraren
erregulazioa

Box 3 | Pathological states involving BBB breakdown or disorder permeability (little or no aquaporin)88–90, it is likely that
the excess metabolic water joins the ISF being secreted
Several pathologies of the CNS involve disturbance of blood–brain barrier (BBB) into the pericapillary space by the endothelium5. ISF out-
function, and, in many of these, astrocyte–endothelial cooperation is also abnormal. flow involves perivascular spaces around large vessels,
Stroke and clearance routes either through the CSF or following
• Astrocytes secrete transforming growth factor-β (TGFβ), which downregulates brain alternative pathways to neck lymphatics.

BHE gaixotasunetan
capillary endothelial expression of fibrinolytic enzyme tissue plasminogen activator Neurotransmitter recycling can also lead to local
(tPA) and anticoagulant thrombomodulin (TM)150. changes in ions and water. Glutamate is the major
• Proteolysis of the vascular basement membrane/matrix151. excitatory transmitter of the brain, and astrocyte proc-
• Induction of aquaporin 4 (AQP4) mRNA and protein at BBB disruption152. esses surrounding synapses can take up glutamate
• Decrease in BBB permeability after treatment with arginine vasopressin V1 receptor through transport proteins (particularly EAAT1 and 2);
antagonist in a stroke model153. the transport is Na+-dependent and accompanied by
net uptake of ions and water, again contributing to
Trauma water clearance at the BBB85. Glutamate is converted
• Bradykinin, a mediator of inflammation, is produced and stimulates production and to glutamine within the astrocyte and recycled to the
release of interleukin-6 (IL-6) from astrocytes, which leads to opening of the BBB102. neurons. The slight astrocytic cell swelling that accom-
Infectious or inflammatory processes panies neuronal activity, resulting from activation by
Examples include bacterial infections, meningitis, encephalitis and sepsis. glutamate or ion uptake, leads to several cellular mech-
• The bacterial protein lipopolysaccharide affects the permeability of BBB tight anisms that contribute to the recovery of ionic balance
junctions. This is mediated by the production of free radicals, IL-6 and IL-1β154. and cell volume, some of which involve elevated intra-
• Interferon-β prevents BBB disruption155. cellular Ca2+ concentration66,91,92. Hence, there are many
links between the signalling and regulatory processes
Multiple sclerosis that occur in the neurovascular unit.
• Breakdown of the BBB97.
• Downregulation of laminin in the basement membrane156. BBB changes in pathology
• Selective loss of claudin 1/3 in experimental autoimmune encephalomyelitis94. In a number of pathologies, the function of the BBB is
altered (BOX 3), and several disorders appear to involve
HIV
disturbances of endothelial–glial interaction. Thus,
• BBB tight junction disruption157,158. the capillaries of many glial tumours are more leaky
Alzheimer’s disease than those of normal brain tissue, either as a result
• Increased glucose transport, upregulation of glucose transporter GLUT1, altered of a lack of inductive factors, or owing to the release
agrin levels, upregulation of AQP4 expression95,159. of permeability factors such as vascular endothelial
• Accumulation of amyloid-β, a key neuropathological feature of Alzheimer’s disease,
growth factor (VEGF). Moreover, the tight junction
by decreased levels of P-glycoprotein transporter expression160. protein claudin 1/3 is downregulated in some brain
tumours93,94.
• Altered cellular relations at the BBB, and changes in the basal lamina and amyloid-β
clearance100. In BBB disruption, agrin is lost from the abluminal
surface of the brain endothelial cells adjacent to astro-
Parkinson’s disease cytic endfeet11; this may contribute to BBB damage in
• Dysfunction of the BBB by reduced efficacy of P-glycoprotein101. Alzheimer’s disease95, and to the redistribution of astro-
Epilepsy
cytic AQP4 in glioblastomas96. Astrocytic AQP4 expres-
sion is upregulated in brain oedema triggered by BBB
• Transient BBB opening in epileptogenic foci, and upregulated expression of
breakdown. Such upregulation could be adaptive in
P-glycoprotein and other drug efflux transporters in astrocytes and endothelium98,99.
helping to clear the accumulating fluid, but the associ-
Brain tumours ated cell swelling would tend to exacerbate the problem
• Breakdown of the BBB161,162. under extreme conditions. Indeed, AQP4–/– mice show
• Downregulation of tight junction protein claudin 1/3; redistribution of astrocyte protection against ischaemic brain oedema48. Some
AQP4 and Kir4.1 (inwardly rectifying K+ channel)20,93,96. chronic neuropathologies such as multiple sclerosis may
involve an early phase of BBB disturbance (involving
Pain
the downregulation of claudin 1/3 (REF. 11)) that precedes
• Inflammatory pain alters BBB tight junction protein expression and BBB neuronal damage, which suggests that vascular damage
permeability108.
can lead to secondary neuronal disorder97.

1 junctions, bradykini

BHE gaixotasunetan NF-κB

ET-1
B2
Bradykinin

3
leading to the releas
amplify the effect by
Tumour necrosis fa
TNFα
Microglial cell permeability by dir
and indirect effects
lL-6 2 production and IL
TNFα •O2–
lL-1β LPS complex immunore
Substance P can exacerbate CNS
[Ca2+]i↑ 5-HT multiple sclerosis b
Histamine activation of already
ATP
some mechanisms e
PGs
B2 Indeed, the ability of
contribute to the lin
tPA
disease106.
tPA It has recently be
Capillary cytes and microglia
Tight 4 pain107. As astrocyt
junction TGFβ↓
connectivity and fo
gested that glia ma
pain sensation. In in
Endothelial from central and pe
cell sue cells and blood
Agrin? such as substance P
K+ (CGRP), serotonin,
AQP4 Glu BBB from both the
For example, the re
Basal lamina Astrocyte 5 concentration or alt
tion protein occludi
Figure 6 | Astroglial–endothelial signalling under pathological conditions. TNFα, histamine an
Examples of astroglial–endothelial signalling in infection or inflammation, stroke or matory pain can also

Odol hodien garapena

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Kraniokanpokoa

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Kraniokanpokoa
Kraniobarnekoa

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Kraniokanpokoa
Kraniobarnekoa
Enbor perpendikularrak

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Kraniokanpokoa
Kraniobarnekoa
Enbor perpendikularrak
Zuhaitzea

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VEGF
Vascular Endothelial Growth Factor

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VEGF-ren ekintzak
I. Indukzioa:
. Proliferazio endoteliala

. Migrazio endoteliala

. Apoptosiaren inhibizioa

II. Ondorio neurotroﬁkoak eta
neurobabesleak

III. Odol hodien iragazkortasuna

VEGF angiogenesian

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Garun odoleztatzea

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