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PMCOL 412 > Blood Brain Barrier > Flashcards

Blood Brain Barrier Flashcards

1
Q

When was the BBB discovered and by who

A

The presence of a “mechanical membrane” that separates blood from brain
was suggested at the beginning of the XX century by Lewandowsky and
Goldman.

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2
Q

How did they discovered the BBB?

A

When dye is added into the blood stream, only blood was stained.
When dye was added into the CSF –> dyes the brain AND CSF

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3
Q

The brain receives __ % of cardiac output

A

20%

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4
Q

What is the neuron to vessel ratio

A

About 1:1. Almost every neuron is perfused by its own vessel

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5
Q

Role of diffusion in distributing nutirents, water, drugs etc. into brain

A

Minimal role

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6
Q

BBB is __ largest discrete area for solute exchange

A

3rd after lung and intestine

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7
Q

If blood flow to brain stops–how long does it take to see damage

A

A stop of seconds, will cause neuronal damage within minutes

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8
Q

The BBB is a ____ and ___ barrier

A

physical and biochemical

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9
Q

Role of BBB

A

to control and regulate the access of molecules from blood to brain to maintain homeostasis of the brain microenvironment

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10
Q

The BBB is made of 3 types of cells…

A

Endothelial cells
Pericytes
Astrocytes

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11
Q

Barrier function is primarily mediated by which cell type(s)

A

Endothelial cells

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12
Q

Development and maintenance of BBB is primnarily mediated by which cell type(s)

A

Pericytes and astrocytes

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13
Q

Other cell types that influence the BBB

A

perivascular inter-neurons and microglia–also contribute to BBB regulation

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14
Q

Regions w/o BBB

A

Area postrema (of medulla)
Circumventricular organs
Regions of the hypothalamus

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15
Q

Structural reason(s) certain brain regions don’t have BBB

A

they have fenestrated capilaries–w/o pericytes and astrocyte ensheathment therefore allowing the passage of hydrophobic molecules, peptides and proteins into the brain

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16
Q

Physiological reason(s) certain brain regions don’t have BBB

A

they need to be able to sample the general circulation (chemoreceptors in area postrema) or release of hormones (hypothalamus)

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17
Q

Feats of BBB

Endothelial cells have _________

A

No fenestrations

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18
Q

Feats of BBB

Transcellular transport through ____ is ____

A

pinocytosis is minimal

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19
Q

Feats of BBB

What system removes small molecules from the endothelial cells before they reach the brain parenchima

A

an efflux transport system ( made up of P-glycoprotein and others)

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20
Q

Feats of BBB

What is the Secondary system consituiting an additional barrier to the BBB

A

the use of enzymatic systems (C450, peptidases, nucleotidases) to inatcivate neuroactive or toxic compounds that enter the brain

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21
Q

Feats of BBB

What ‘seals’ the paracellular pathway

A

Tight junctions

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22
Q

What is a tight junction

A

an adhesion complex found between adjacent endothelial cells that seals the paracellualr pathway-restricting movement b/t cells

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23
Q

Because of tight junctions ____ transport is negligible at the BBB

A

paracelluar transport

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24
Q

Additional role of tight junctions in BBB

A

Maintaining highly polarized state of BBB endothelial cells by segregating the apical (luminal) and basal (abluminal) domains of the endothelial cell memb

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25
Q

What structural transmembrane proteins responsible for tight junction regulation?

A

Occludin

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26
Q

What structural transmembrane proteins responsible for tight junction “tightness”?

A

Claudins

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27
Q

What structural transmembrane proteins responsible for tight junction stability and maintenance?

A

Junctional adhesion molecules (JAMs)

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28
Q

What cytoplasmic accessory proteins responsible for tight junction’s ability to anchor transmembrane proteins to the cytoskeleton and modulate junction “tightness”?

A

Zonula occludens proteins 1 and 2 (ZO-1 and ZO-2)
and cingulin

have a regulatory function in determining tightness of the TJs

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29
Q

How do tight junctions effect transendothelial electrical resistance (TEER)

A

Tight junction restricts the movement of water and ions (Na+ and Cl-) therefore increasing TEER

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30
Q

TEER (transendothelial electrical reistance)

A

Measure of the resistance to an electrical current passed across the endothelial monolayer as a measure of ionic permeability

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31
Q

How peripheral TEER compares to cerebral TEER

A

TEER 2-20 ohms/cm2 peripheral microvessels
>1000 ohms/cm2 in micro microvessels
High TEER due to tight junctions

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32
Q

TEER and tight junction

A

restrict ion and water flow –> increase TEER

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33
Q

BBB is present in…

A

all vertebrates

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34
Q

How BBB differs across species

A

species differences in postnatal murations leads to differences in amount of drugs being able to reach the brain during development

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35
Q

In humans BBB developement is completed by

A

6 months of age (postnatal)

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36
Q

In humans BBB development starts

A

During the first trimester of fetal life (completed by 6 months postnatally)

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37
Q

Permeability and drug effects on neonates altered by:

A

differently than to adults due to incomplete BBB–should take into consideration higher permeability of fetal and neonate BBB

38
Q

Role of neural stem cells in BBB development

A

neural stem cells produce Wnt molecules that stimulate endothelial cells of the brain to express BBB-related molecules

39
Q

Pericytes and astrocytes contribute to

A

BBB development, maturation and MAINTENANCE

40
Q

WNT

A

released by neural stem cells

stimulate production BBB

41
Q

Astrocyte location

A

astrocyte end-feet completely surround microvessels

42
Q

Astrocyte roles

A

Transport of nutrients to brain
regulation of BBB props
regulation of local bloodflow

43
Q

Neurovascular coupling

A

synchronizes neuronal metabolic demands to local cerebral blood flow regulation (increased activity, increased blood flow)
done by astrocytes

44
Q

How astrocytes participate in neurovascular coupling

A

detect glutamate-depending synaptic activity and respond by producing prosteoids (bioactive lipids) that cause vasodlation (which increases blood flow to the area of higher activity)

45
Q

Effects of Astrocyte-produced cytokines and growth factorss

A

contribute to tighter TJ + induction of transported expression (p-glycoproteon and GLUT-1)
for the maintenance of mature barrier props

46
Q

In-vitro experiments of endothelial plus astrocytes vs without astrocytes–differneces

A

TEER increased when co-cultured w/ astrocytes
Endothelial cells alone–some barrier resistance (suggest endothelial cells themselves already have some)
Endothelial cells w/ astrocytes – increased barrier resistance

47
Q

Where are pericytes

A

juxtaposed to the endothelial cells and together with them form a matrix of extracellular proteins (basal lamina) that surrounds the vessel

48
Q

How do pericytes get recruited

A

Endothelial cells secrete platelet-dervied growth factor B (PDGF-B) recruits them closer to the enodthelial cells and leads to vascular maturation

49
Q

platelet-dervied growth factor B (PDGF-B)

A

Secreted by endothelial cells to recruit pericytes

50
Q

Pericytes produce ____ to induce barrier functions

A

Angiotensin 1 (ANG-1) and TGF-beta

51
Q

The actions of pericytes on BBB props is mediated by their ability to _____ and _____

A

Polarize astrocyte endfeet and limit endothelial transcytosis

52
Q

Pericyte to endothelium in brain vs muscle

A

1:3 versus 1:100

53
Q

Pericytes roles (simplified)

A

Provide mechanical stability release Ang1, TGF-beta to induce barrier function
Also have contractile function (control blood flow with contraction/relaxation)

54
Q

How pericytes control blood flow

A

Via their contractile function (control blood flow with contraction/relaxation)

55
Q

In-vitro models best reproduce true BBB properties if they have

A

both astrocytes and pericytes

will have high TEER (as seen in vivo)

56
Q

BBB transport: no ____ transport, exhange of molecules may occur through _____ or _______

A

No paracellular transport and minimal pinocytosis

Mainly through: lipid-mediated diffusion or catalysed transport

57
Q

What undergoes Lipid-mediated free diffusion

A

lipophilic compounds with a molecular mass <400-500 Da

i.e. free diffusion of small lipophillic molecules

58
Q

Catalysed transport–3 types

A

facilitative transport
active-efflux transport
receptor-mediated transcytosis

59
Q

The permeability of the BBB is directly proportional to (in most cases)…

A

the lipid solubility of the substance (measured by the oil-water partition coefficient)
More high-philic, more permeable

60
Q

Exception– higher than expected permeability

A

Some hydrophilic molecules (ex. D-glucose) are readily taken up by selective endothelial transport–higher than predicted due to selective transport

61
Q

Exception-lower than expected permeability

A

Drugs with very high oil-water parition coefficients need to be bound to albumin in blood–> decrease delivery to brain

62
Q

(Oil-water) Partition coefficient

A

ratio of concentrations of a compund in the two phases of a mixture of two immiscle solvents, usually water and octanol, at equilibrium

63
Q

BBB transport of MACROmolecules

A

either: receptor-mediated transcytosis OR
adsorptive-mediated transcytosis
BOTH forms of trancytosis

64
Q

Receptor-mediated transcytosis: mechanism

A

receptor and bound ligand are internalized and move through the cytoplasm to the abluminal side where the ligand is exocytosized

65
Q

Receptor-mediated transcytosis: ligands

A 
transferrin
IgG
insulin
leptin
TNF-alpha, EGF
66
Q

Adsorptive-mediated transcytosis: mechanism

A

cationised albumin interacts with negative cell membrane allows passage through endothelial cells

67
Q

The ability of the sorting endosome to route away from _____ is a special feature of the BBB

A

LYSOSOMES

in contrast–in the periphery contents of primary endosomes are routed to the acidic lysosome for enzymatic degradation

68
Q

P-Glycoprotein (aka MDR1 and ABCB1)–structure

A

transmembrane protein charcteriszed by 2 homologous halves, each with six transmembrane domains and a typical ATP-binding domain

69
Q

P-Glycoprotein role

A

hydrolizes ATP to transport molecules across the cell membrane (export bad things from the brain)
expressed in many normal tissues, where together with xenobiotic metabolizing enzymes, it acts to protect the body from potentially toxic xenobiotics

70
Q

________ is one of the most important transporters for drug disposition in humans

A

P-glycoprotein

Moves drugs out of tissues including out of the brain

71
Q

P-glycoprotein: props of good substrates

A

hydrophillic or antipathic

BROAD range

72
Q

Trouble with P-glycoprotein

A

Pumps drugs out of the brain–good if target is the periphery (won’t have neural effects)
BAD if brain is the target –> trouble with neuropharmacology

73
Q

P-glycoprotein mediated efflux

A

1) Substrate partitions the bilayer from outside the cell to the inner leaflet and enters the internal drug-binding pocket through an open portal.
2) The AA residues in the drug binding site stabilize the protein-substrate interaction.
3) Upon ATP binding to the nucleotide-binding domain –> P-gp changes conformation and forces the substrate out

74
Q

P-gp affcets drug absorption and tissue distribiton through

A

1) limited drug absorption (limits drug entry in gut)
2) Active drug elimination (once in circulation promotes elimination into urine)
3) Limited drug distribution into tissues (limits entry into sensitive tissues–ex. brain or testes)
Effects drug efficacy by decreasing its concentration

75
Q

MDR-2 gene polymorphism’s role in CNS disease

A

these polymorphisms affect protein expression/activity incfluencing individual response to treatments and disease progression

76
Q

Examples of MDR-2 gene polymorphism’s role in CNS disease

A

pesticide-induced PD associated with certain MDR-1 polymorphisms (pesticides that are usually removed are not –> cause PD);
Drug-resistant epilepsy (drugs removed from the brain –> non effective)

77
Q

Dysfunction of BBB contributes to development and progression of

A 
Alzheimers 
PD
HIV-related dementia
ALS
MS
78
Q

Disruption of the BBB occurs due to these pathologies

A

Stoke and brain injuries
inflammation
brain tumours

79
Q

Brain regions w/o BBB

A

Area postrema
subfornical organ
pineal gland
neurohypophysis

80
Q

2 roles of tight junctions

A
  • restricting paracellular transport
  • maintaining the polarity of endothelial cells (by segregating the apical and basal domains of te endothelial cell memb)
81
Q

BBB Transport systems

A

1) facilitative transporters
2) active Na+-dependent transporters
3) facilitative transporters on the luminal membrane
4) ATP-binding cassette (ABC) transporters

82
Q

Facilitative transporters can be on…

A

both membranes or only on the luminal membrane

83
Q

Facilitative transporters on both membranes examples:

A

GLUT-1, L system MCT-1

84
Q

Facilitative transporters on the luminal membranes examples:

A

Xg-transporter
N-transporter
Glu and Gln transporters
follows conc gradient but extrude aa’s accumulated in the endothelial cells

85
Q

Facilitative transporters mechanism

A

move molecules following their concentration gradient (high to low)

86
Q

Active Na+-dependent transporters–mechanism

A

on the abluminal membrane transport molcules against their graident via co-transport with Na that is then pumped out by the Na+/K+ pump

87
Q

Active Na+-dependent transporters–examples

A

glutamate and glycine aa’s pumped out

88
Q

ATP-binding cassette (ABC) transporters–examples

A

P-glycoprotein, MRP

89
Q

Active Na+-dependent transporters–purpose

A

efflux metabolites, drugs and xenobiotics out of the brain and into the blood

90
Q

P-GP expression is high in

A

enterocytes (gut) , kidney cells, heptocytes, placenta and BBB
affects how drugs abosrp and distribute in the body

PMCOL 412 (35 decks)

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