1
1




Garun odoleztatzea
1




Garun odoleztatzea
                        Enrike G. Argandoña
    Neurozientzia kliniko eta esperimentaleko laborat...
Garun odoleztatzea




                     2
Garun odoleztatzea


 Arteria-sistema aferentea



                        2
Garun odoleztatzea


 Arteria-sistema aferentea
 Bena-sistema eferentea

                          2
3




    Garun odoleztatzea
3




    Garun odoleztatzea

     Garun bolumenaren %1
3




    Garun odoleztatzea

     Garun bolumenaren %1
     Bihotz gastuaren %20
3




    Garun odoleztatzea

     Garun bolumenaren %1
     Bihotz gastuaren %20
     Energiaren %65
4


    Garun odoleztatzea
    Babes mekanismoak
4


       Garun odoleztatzea
       Babes mekanismoak


    Zirkulazio sistemikoaren kontrola
4


       Garun odoleztatzea
       Babes mekanismoak


    Zirkulazio sistemikoaren kontrola
    Garun-odol basoen autor...
4


       Garun odoleztatzea
       Babes mekanismoak


    Zirkulazio sistemikoaren kontrola
    Garun-odol basoen autor...
5




    Garun odoleztatzea
5




    Garun odoleztatzea
8
8
8
8
Garun barneko odol hodiak




                            9
Garun barneko odol hodiak


 Arteriolak (50-100 µm)




                            9
Garun barneko odol hodiak


 Arteriolak (50-100 µm)
 Arteriola terminalak (10-100µm)




                                 ...
Garun barneko odol hodiak


 Arteriolak (50-100 µm)
 Arteriola terminalak (10-100µm)
 Benulak (± 30 µm)


                ...
Garun barneko odol hodiak


 Arteriolak (50-100 µm)
 Arteriola terminalak (10-100µm)
 Benulak (± 30 µm)
 Kapilareak (<30 µ...
10




     Garun odoleztatzea
10




     Garun odoleztatzea

       Sare kapilarea
10




     Garun odoleztatzea

       Sare kapilarea
       Barrera hematoentzefalikoa
10




     Garun odoleztatzea

       Sare kapilarea
       Barrera hematoentzefalikoa
        Egitura-mekanismoak
10




     Garun odoleztatzea

       Sare kapilarea
       Barrera hematoentzefalikoa
        Egitura-mekanismoak
      ...
Garun-barrerak
Garun-barrerak
12



     Barrera hematoentzefalikoa
12



     Barrera hematoentzefalikoa
12



     Barrera hematoentzefalikoa
13



     Barrera hematoentzefalikoa
13



     Barrera hematoentzefalikoa
Garraio motak
Garraio motak
a                           b               c                                 d                         e
Pa...
15



      Barrera hematoentzefalikoa
 Zelulak
15



                    Barrera hematoentzefalikoa
                                        REVIEWS



                  ...
Zelularteko seinaleak BHEn
at the BBB is observed in starvation and hypoxia53,54.
                   Zelularteko seinaleak BHEn
Blood                ...
17




Garun endotelioa
17




Garun endotelioa

                   Mitokondria ugari
17




Garun endotelioa

                   Mitokondria ugari
                   Pinozitosiaren gabezia
17




Garun endotelioa

                   Mitokondria ugari
                   Pinozitosiaren gabezia
                  ...
17




Garun endotelioa

                   Mitokondria ugari
                   Pinozitosiaren gabezia
                  ...
18




Astroglia
18




Astroglia

            BHEren indukzioa
18




Astroglia

            BHEren indukzioa
            BHEren
            mantenimendua
18




Astroglia

            BHEren indukzioa
            BHEren
            mantenimendua
            Tonu baskularraren...
18




Astroglia

            BHEren indukzioa
            BHEren
            mantenimendua
            Tonu baskularraren...
18




Astroglia

            BHEren indukzioa
            BHEren
            mantenimendua
            Tonu baskularraren...
19



     Perizitoak
19



     Perizitoak
19



     Perizitoak


                  Nortasun iluna
                  Pluripotentzialak
                  Parte hartz...
Lotura sendoak (TJ)
Lotura sendoak (TJ)
Apical membrane

     Cingulin, JACOP, PAR3/6,
     CASK, 7H6, Itch, MUPP1,                              Claudin 3, 5, 12
...
Lotura sendoak (TJ)
Lotura sendoak (TJ)
Barrera hematoentzefalikoa
Barrera hematoentzefalikoa
Barrera hematoentzefalikoa
Barrera hematoentzefalikoa
24



     Aktina
24



     Aktina
25


     Iragazkortasun mikrobaskularraren
     erregulazioa
25


     Iragazkortasun mikrobaskularraren
     erregulazioa
BHE gaixotasunetan
Box 3 | Pathological states involving BBB breakdown or disorder                            permeability (little or no aqua...
BHE gaixotasunetan
1                                                                                  junctions, bradykini

BHE gaixotasuneta...
28




     Kapilare-sarea
28




     Kapilare-sarea
Odol hodien garapena




                       29
Odol hodien garapena

Kraniokanpokoa




                        29
Odol hodien garapena

Kraniokanpokoa
Kraniobarnekoa




                        29
Odol hodien garapena

Kraniokanpokoa
Kraniobarnekoa
 Enbor perpendikularrak



                          29
Odol hodien garapena

Kraniokanpokoa
Kraniobarnekoa
 Enbor perpendikularrak
 Zuhaitzea


                          29
Odol hodien garapena
Odol hodien garapena
Odol hodien garapena
0 dpn




        34
7 dpn




        35
14 dpn




         36
21 dpn




         37
60 dpn




   38
40


VEGF
Vascular Endothelial Growth Factor
40


VEGF
Vascular Endothelial Growth Factor
40


VEGF
Vascular Endothelial Growth Factor
41




VEGF-ren ekintzak
41




VEGF-ren ekintzak
41




VEGF-ren ekintzak
I. Indukzioa:
    . Proliferazio endoteliala

  . Migrazio endoteliala

  . Apoptosiaren inhibizi...
VEGF-ren hartzaileak
VEGF-ren hartzaileak
VEGF angiogenesian




                     43
VEGF angiogenesian




                     43
VEGF angiogenesian
VEGF angiogenesian
Garun odoleztatzea
Garun odoleztatzea
Garun odoleztatzea
Garun odoleztatzea
Garun odoleztatzea
Garun odoleztatzea
Garun odoleztatzea
Garun odoleztatzea
Garun odoleztatzea
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Garun odoleztatzea

  1. 1. 1
  2. 2. 1 Garun odoleztatzea
  3. 3. 1 Garun odoleztatzea Enrike G. Argandoña Neurozientzia kliniko eta esperimentaleko laborategia (LaNCE) Euskal Herriko Unibertsitatea http://www.ehu.es/LaNCE Iruñea. Uztaila 2006
  4. 4. Garun odoleztatzea 2
  5. 5. Garun odoleztatzea Arteria-sistema aferentea 2
  6. 6. Garun odoleztatzea Arteria-sistema aferentea Bena-sistema eferentea 2
  7. 7. 3 Garun odoleztatzea
  8. 8. 3 Garun odoleztatzea Garun bolumenaren %1
  9. 9. 3 Garun odoleztatzea Garun bolumenaren %1 Bihotz gastuaren %20
  10. 10. 3 Garun odoleztatzea Garun bolumenaren %1 Bihotz gastuaren %20 Energiaren %65
  11. 11. 4 Garun odoleztatzea Babes mekanismoak
  12. 12. 4 Garun odoleztatzea Babes mekanismoak Zirkulazio sistemikoaren kontrola
  13. 13. 4 Garun odoleztatzea Babes mekanismoak Zirkulazio sistemikoaren kontrola Garun-odol basoen autorregulazioa
  14. 14. 4 Garun odoleztatzea Babes mekanismoak Zirkulazio sistemikoaren kontrola Garun-odol basoen autorregulazioa Fluxuaren banaketa
  15. 15. 5 Garun odoleztatzea
  16. 16. 5 Garun odoleztatzea
  17. 17. 8
  18. 18. 8
  19. 19. 8
  20. 20. 8
  21. 21. Garun barneko odol hodiak 9
  22. 22. Garun barneko odol hodiak Arteriolak (50-100 µm) 9
  23. 23. Garun barneko odol hodiak Arteriolak (50-100 µm) Arteriola terminalak (10-100µm) 9
  24. 24. Garun barneko odol hodiak Arteriolak (50-100 µm) Arteriola terminalak (10-100µm) Benulak (± 30 µm) 9
  25. 25. Garun barneko odol hodiak Arteriolak (50-100 µm) Arteriola terminalak (10-100µm) Benulak (± 30 µm) Kapilareak (<30 µm) 9
  26. 26. 10 Garun odoleztatzea
  27. 27. 10 Garun odoleztatzea Sare kapilarea
  28. 28. 10 Garun odoleztatzea Sare kapilarea Barrera hematoentzefalikoa
  29. 29. 10 Garun odoleztatzea Sare kapilarea Barrera hematoentzefalikoa Egitura-mekanismoak
  30. 30. 10 Garun odoleztatzea Sare kapilarea Barrera hematoentzefalikoa Egitura-mekanismoak Mekanismo metabolikoak
  31. 31. Garun-barrerak
  32. 32. Garun-barrerak
  33. 33. 12 Barrera hematoentzefalikoa
  34. 34. 12 Barrera hematoentzefalikoa
  35. 35. 12 Barrera hematoentzefalikoa
  36. 36. 13 Barrera hematoentzefalikoa
  37. 37. 13 Barrera hematoentzefalikoa
  38. 38. Garraio motak
  39. 39. 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
  40. 40. 15 Barrera hematoentzefalikoa Zelulak
  41. 41. 15 Barrera hematoentzefalikoa 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-
  42. 42. Zelularteko seinaleak BHEn
  43. 43. 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
  44. 44. 17 Garun endotelioa
  45. 45. 17 Garun endotelioa Mitokondria ugari
  46. 46. 17 Garun endotelioa Mitokondria ugari Pinozitosiaren gabezia
  47. 47. 17 Garun endotelioa Mitokondria ugari Pinozitosiaren gabezia Fenestrazioen gabezia
  48. 48. 17 Garun endotelioa Mitokondria ugari Pinozitosiaren gabezia Fenestrazioen gabezia
  49. 49. 18 Astroglia
  50. 50. 18 Astroglia BHEren indukzioa
  51. 51. 18 Astroglia BHEren indukzioa BHEren mantenimendua
  52. 52. 18 Astroglia BHEren indukzioa BHEren mantenimendua Tonu baskularraren kontrola
  53. 53. 18 Astroglia BHEren indukzioa BHEren mantenimendua Tonu baskularraren kontrola BHEren egitura?
  54. 54. 18 Astroglia BHEren indukzioa BHEren mantenimendua Tonu baskularraren kontrola BHEren egitura?
  55. 55. 19 Perizitoak
  56. 56. 19 Perizitoak
  57. 57. 19 Perizitoak Nortasun iluna Pluripotentzialak Parte hartzea angiogenesian eta BHEren ontzean
  58. 58. Lotura sendoak (TJ)
  59. 59. Lotura sendoak (TJ)
  60. 60. 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
  61. 61. Lotura sendoak (TJ)
  62. 62. Lotura sendoak (TJ)
  63. 63. Barrera hematoentzefalikoa
  64. 64. Barrera hematoentzefalikoa
  65. 65. Barrera hematoentzefalikoa
  66. 66. Barrera hematoentzefalikoa
  67. 67. 24 Aktina
  68. 68. 24 Aktina
  69. 69. 25 Iragazkortasun mikrobaskularraren erregulazioa
  70. 70. 25 Iragazkortasun mikrobaskularraren erregulazioa
  71. 71. BHE gaixotasunetan
  72. 72. 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.
  73. 73. BHE gaixotasunetan
  74. 74. 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
  75. 75. 28 Kapilare-sarea
  76. 76. 28 Kapilare-sarea
  77. 77. Odol hodien garapena 29
  78. 78. Odol hodien garapena Kraniokanpokoa 29
  79. 79. Odol hodien garapena Kraniokanpokoa Kraniobarnekoa 29
  80. 80. Odol hodien garapena Kraniokanpokoa Kraniobarnekoa Enbor perpendikularrak 29
  81. 81. Odol hodien garapena Kraniokanpokoa Kraniobarnekoa Enbor perpendikularrak Zuhaitzea 29
  82. 82. Odol hodien garapena
  83. 83. Odol hodien garapena
  84. 84. Odol hodien garapena
  85. 85. 0 dpn 34
  86. 86. 7 dpn 35
  87. 87. 14 dpn 36
  88. 88. 21 dpn 37
  89. 89. 60 dpn 38
  90. 90. 40 VEGF Vascular Endothelial Growth Factor
  91. 91. 40 VEGF Vascular Endothelial Growth Factor
  92. 92. 40 VEGF Vascular Endothelial Growth Factor
  93. 93. 41 VEGF-ren ekintzak
  94. 94. 41 VEGF-ren ekintzak
  95. 95. 41 VEGF-ren ekintzak I. Indukzioa: . Proliferazio endoteliala . Migrazio endoteliala . Apoptosiaren inhibizioa II. Ondorio neurotrofikoak eta neurobabesleak III. Odol hodien iragazkortasuna
  96. 96. VEGF-ren hartzaileak
  97. 97. VEGF-ren hartzaileak
  98. 98. VEGF angiogenesian 43
  99. 99. VEGF angiogenesian 43
  100. 100. VEGF angiogenesian
  101. 101. VEGF angiogenesian

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