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BBB Flashcards

1
Q

What does the BBB do?

A

At simplest, separates brain-fluid compartments blood from extracellular fluid of brain (cerebrospinal fluid and interstitial fluid)

It shields brain from anything / any changes in plasma that the brain doesn’t want

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2
Q

Why do you not want XS neurotransmitters in the brain and give an example?

A

Reduce seizure risk

Don’t want spikes and troughs in neurotransmitters like glutamic acid- you want the brain to be controlled and tightly regulated.

Glutamic acid levels increase after a protein meal.

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3
Q

What was Goldmann’s experiment (discovery of BBB)?

A

Injected Typan blue IV which stained the body and not the CNS. When injected intrathecally, the body was unstained and the CNS was stained.

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4
Q

What are the 3 reasons why delivering drugs to the brain is a problem for the pharma industry?

A
  • Failures treating brain tumours and neurodegeneration- less than 5% of drugs trialled have any clinical benefit as the majority do not pass the BBB
  • Costly
  • Pharma must not only develop drugs for disease, but ways to cross the BBB
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5
Q

What are the 5 reasons why we have a BBB?

A
  1. Ion regulation for optimal neural signalling. Potassium is most important followed by sodium and calcium. Nerve cells will only fire action potentials with certain ion level thresholds.
  2. Molecular traffic. Keeps toxins out to prevent cell death in the brain.
  3. Low protein in the ECF compared to the blood. Protein is needed for cell proliferation. We don’t want over proliferation in the brain as the new cells will press on the neurons resulting in tumours. Neurons cannot divide.
  4. Preserves neurotransmitter signalling; separates CNS transmitters form peripheral transmitters- you don’t want e.g. glutamic acid, adrenaline and NA firing random action potentials in the brain
  5. ‘Silent’ immune surveillance. Keeps leukocytes out, to limit inflammation. The brain has its own immune system with astroglia. In the peripheral system, the immune system induces inflammation and oedema and you do not want that in the confined skull space.
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6
Q

You can have regions in the brain without a barrier. What are these called and why is it useful?

A

Circumventricular organs

e.g. posterior pituitary

Neurones want to secrete hormones directly into the blood e.g. growth hormone, prolactin and melatonin

Neurones want to sample the plasma to detect ion levels or presence of toxins

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7
Q

What are the 4 key areas of difference in the levels of compounds and pH in the brain vs blood?

A
  1. Lower K+ 2.9 mM

Allows neurons to achieve a lower resting potential (-100 mV vs -90 mV in peripheral). Meaning they are unlikely to spontaneously fire. In the periphery this causes twitches, in the CNS it causes seizures. When people have seizures, in these focal areas potassium levels are higher. In children with fever, they can have febrile reversible seizures as the BBB opens up a bit more and ions get in

  1. Slightly more acidic than plasma 7.3 vs 7.4

Speeds up the Na/K pump’s ability to repolarise and restore ion concentraions (following action potential)

  1. Low protein (albumin) 6 g/dL vs 0.02 g/dL

Preventing cell proliferation, water retention and brain oedema. Water tends to follow protein and you do not want extra water in enclosed skull

  1. Low calcium (1.2 mM) and glutamate (0.5 micromol)

Both are key drivers of ‘excitotoxicity’ in nerve cells. Can cause irreversible neurodegeneration (AD) where membranes become more permeable and enzymes break down the cell. Strategy of treating AD- block glutamate receptors

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8
Q

Why is there a rich blood supply in the brain?

A

The requirements for oxygen and glucose is 7 times higher than other organs.

If unravelled, capillaries in the brain would be very low and have a high SA.

They are so dense and close together and are wide enough just to let a RBC through and nothing else.

The rich capillary network is need for constant supply of nutrients.

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9
Q

What is the choroid plexus and what does it do?

A

Cells that produce CSF in lateral, 3rd and 4th ventricles of the brain. they also act as a lymphatic system for the brain to clear out toxins (filtration)

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10
Q

What the the 3 different barrier types in BBB?

A
  1. Physical barrier
  2. Transport barrier
  3. Metabolic barrier
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11
Q

What is the physical barrier of the BBB?

A

The point at which the endothelial cells join, there is a specialised set of proteins that zip them together (tight junction proteins) so endothelial cells cannot be separated

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12
Q

What cells are critical for tight junction formation?

A

Astrocytes - possible they secrete factors from end feet

They are not the barrier, they just sit very close to it and help make it.

If you start losing astrocytes, you lose tight junctions and similarly, if you put astrocytes elsewhere in the body, tight junctions will start to form

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13
Q

What does the basement membrane do?

A

Anchor endothelial cells and tells them which side is the brain side

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14
Q

What is the other type of junction found throughout the body but not in BBB?

A

Adherens junctions- simple linking of cells using cadherin

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15
Q

What are tight junctions made up of?

A

Complex protein structure unique to the brain

Includes proteins such as occludin, claudin and zonula occludens (ZO)

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16
Q

What cells are susceptible to brain tumours?

Why are neurons not?

A

Astrocytes and glia

Neurones are post mitotic so cannot divide

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17
Q

How can you measure how tight these tight junctions are?

A

Through how many ions e.g. sodium can get through

In resistance (Ohms cm^2)

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18
Q

What is the resistance of a muscle capillary vs brain capillary?

A

40 Ohms cm^2

8000 Ohms cm^2

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19
Q

What kind of drugs can get through the BBB and give examples?

A
  • Small (<400 Da) and lipid soluble (Log P > 1)
  • Drugs related to amphetamines / ecstasy and cannabinoids
  • Legal highs developed as small very lipophilic molecules. (no therapeutic indication as they disrupt normal function of nerve cells at level of the synapse)
  • Oxygen, alcohol, caffeine, nicotine, opiates, anaesthetics
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20
Q

What % of small molecule drugs can pass through BBB?

A

2%

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21
Q

What is the transport barrier

What are the 3 types of these barriers?

A

Efflux transporters use ATP to prevent some lipid soluble compounds entering the CNS (generally anything > 3/400 Da)

  • P-glycoprotein blocks out the most drugs
  • BCRP (breast cancer resistance protein)
  • MRP (multi-drug resistance proteins) range of these, 1, 2, 4,5,7

(MRP 1 moves things in opposite direction – keeps things in brain)

Prevent drugs (chemotherapy ABX, statins) getting through

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22
Q

How do efflux transporters know to kick a compound out?

A

They don’t recognise certain groups, they only use lipophilicity and drug size to see if it will pass through

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23
Q

What is a disadvantage of the efflux transporters and how is this overcome?

A

They are only as good as how many there are, however they are all able to up-regulate their expression if exposed to more of a compound and then produce more transporters.

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24
Q

What is the metabolic barrier?

What is the main metabolic enzyme in BBB?

A

The capability of the BBB to start metabolising drugs, even as they pass through the capillary endothelial cells before they get to the neurons

  • CYP450 is major one in BBB
  • Some metabolic enzymes are related to disease
  • CYP metabolise a vast array of compounds, including centrally acting drugs, neurotoxins and neurotransmitters. E.g. 2E1 breaks down alcohol

They can break down compounds to give to the brain as well:

  • They break down endogenous compounds, (e.g. arachidonic acid, etc),
  • So endothelial cells can use the products themselves
  • Or to pass metabolised contents to the neurons. (neurons rather have lactate than glucose) – like a baby needing broken down food
  • CYPs can be upregulated if exposed to pollutants
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25
Q

What are the metabolic enzymes found in the astrocyte end feet?

A

CYP2J2 and 2U1

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26
Q

What are the main metabolic enzymes found in the neurones?

A

CYP46A1

and 2E1 is exclusive to neurone

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27
Q

What mutated metabolic enzyme is linked to dementia?

A

Mutated CYP2J2 (which usually metabolises arachidonic acid to active vasodilators to increase blood flow in the brain) linked to dementia

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28
Q

What kind of transporters take up things into the brain?

A

Uptake transporters, unidirectional

Different transporters for different types of amino acids

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29
Q

Where are uptake transporters located and why?

A

Blood side as they are polarised

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30
Q

What are 4 examples of uptake transporters?

A

Glut 1 - glucose

Mct1 - lactate

Lat1 - leucine (neutral amino acid)

Tfr -transferrin

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31
Q

What is transferrin?

A

Transferrin is a peptide used for regulating iron. It is large, gets through by aid of the TFr iron carrier

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32
Q

What are the 5 ways of transport across the BBB and what do they move across?

A
  1. Paracellular aqueous pathway
    - Very small water-soluble agents e.g. ions
  2. Transcellular lipophilic pathway - Small lipid soluble agents
  3. Transport proteins
    - Carrier mediated uptake of many essential water-soluble compounds (glucose, amino acids, small peptides) – clinical significance of delivery of L-dopa in PD
  4. Receptor meditated transcytosis (RMT)
    - Specific uptake of larger molecules (transferrin, insulin, lipoproteins, cytokines. Hijacked by viruses
  5. Adsorptive mediated transcytosis (AMT)
    - Non-specific uptake of larger (+) charged proteins e.g. albumin
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33
Q

How can receptor mediated transcytosis be used as a possible drug therapy, especially in AD?

A

Possible drug therapy where you hijack inactive virus with drug to trigger this type of mechanism

Can be bi-directional as it has been found to remove amyloid beta peptide from the brain, possible AD therapy

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34
Q

How are neurones and capillaries connected?

A

Astrocytes and pericytes

35
Q

What are astrocytes and pericytes?

A

Astrocytes:

  • Connect an endothelial cell to the synapse of a neuron.
  • Not touching but is more like what happens between synapses
  • Help to buffer and redistribute potassium, carbon dioxide and water away from site of activity (neurones) to the BBB for removal
  • They are not excitable cells however when they pick up a neurotransmitter, they release calcium and vasoactive substances - stimulates the pericyte which contracts and dilates. (So if the synapse is active, pericyte will dilate and capillary blood flow will increase to meet the higher glucose and oxygen demands)

Pericytes:

  • Behave a little like smooth muscle cells.
  • They have actin and myosin in them
36
Q

The blood flow in the brain can be measured with what machine and how is this advantageous in diagnostics?

A
  • Functional MRI
  • Small changes in blood flow can be measured to identify regions of neuronal brain activity
  • Active areas will have increased blood flow
  • In neurodegenerative diseases, pericytes will remain constricted – reduced blood flow in that area which you can see on the MRI
  • If you lose the neurones, you start to lose the capillaries as well
37
Q

How many times a day does the CSF fluid get replaced per day and what does this mean for drugs in the brain?

A

4 times a day so any drug you get in the brain won’t stay there for long

For this reason, BBB drugs need a dosing of at least BD

38
Q

What are the similarities between the BBB and the blood CSF barrier?

A
  • Physical barrier-

With the blood CSF barrier, tight junctions are not as tight as BBB so the endothelial cells are more leaky. They still restrict movement however

  • Transport barrier - can remove toxins, large molecules and pass them back into the blood
39
Q

What is the volume of CSF in the brain?

A

150 mL

40
Q

What is the secretion rate of CSF production?

A

0.5 mL/min

41
Q

Compare the CSF composition to the plasma

A

CSF composition similar to plasma but protein, glucose, amino acids are lower

42
Q

What does the CSF do?

A

CSF acts as a cushion that protects the brain from shocks and trauma

It also plays an important role in the homeostasis and metabolism of the CNS

43
Q

How is CSF produced and what is the driving force?

A

Water follows net ion transport set up by sodium potassium ATPase in apical membrane (CSF side)

  • Sodium potassium pump is responsible for pumping sodium into the ventricles (ATP dependent against concentration gradient) with water following- this is what drives the flow
44
Q

What happens with the production of CSF in AD?

A

Down regulation production of CSF

45
Q

What happens when there is a block of CSF flow?

A

HYDROCEPHALUS and cognitive impairment

46
Q

What is hydrocephalus?

What could cause this?

A
  • Dilated ventricles swelling of the brain, increased intercranial pressure, squeezing the brain against the cranium.
  • Clinically: if the flow is interrupted, generally not because the Na pump isn’t working anymore, but because there is some block in pipework. Often where the lateral ventricles join and go to third.
  • Could be a tumour, calcium, or glycated proteins (as in diabetes).
47
Q

What are the 2 types of hydrocephalus?

A

Non-communicating (obstructive)

  • Usually due to blockage of aqueduct of Sylvius – congenital
  • Brain tumour at any age

Communicating (non-obstructive)

  • Impaired CSF reabsorption and blockage of CSF flow in subarachnoid space or villi
48
Q

What is the treatment for hydrocephalus?

A

Shunt (drainage tube) between brain ventricles and abdominal cavity

49
Q

What is CSF flow aided by?

When is CSF flow higher and how is this clinically significant?

A

Pulsatile flow (cardiac cycle) and circadian rhythm

CSF flow is not smooth/slow and steady

Flow is higher at night (and with anaesthesia) therefore, want to give drugs in the morning if you want them to stay in the brain as minimum CSF flow is midday and won’t be cleared as quickly

50
Q

How could you make a drug stay longer in the CNS?

A

Use larger size as it takes longer to clear but BBB crossing is hard. Many new drugs are biologics now but too large and hydrophilic

Bind drug to neurone/glia

Cannot just breakdown the barrier

51
Q

BBB is associated with many diseases. What causes BBB breakdown?

A
  • Stroke
  • Epilepsy
  • Traumatic brain injury
  • MS
  • Bacterial meningitis
52
Q

What is the consequence of BBB breakdown (conditions)?

A
  • AD
  • HIV related dementia
  • Cerebral malaria
  • Brain tumours
  • PD
  • Depression and schizophrenia
53
Q

Treatment of brain tumours have not changed for 20-30 years as new treatments have not added QOL. True or false?

A

True

54
Q

Tumour treatment generally is targeted to 3 areas. What are these?

Which one is the only effective way currently for brain tumours?

A
  1. Inhibit Growth factors receptors. Tumours tend to over express growth factor receptors critical for glioma growth and proliferation, which picks up growth factors and drives proliferation. (true in brain as well).
  2. Disrupt intracellular signalling and cause apoptosis (initiate cell death).
  3. Most traditional way (and only currently effective way in brain, at the moment) is to block cell division. Can do this by preventing mitosis, at various stages (most often by inhibiting DNA copying)
55
Q

Why don’t current cancer regimens really work for CNS tumours?

A

Physical barrier Large hydrophilic drugs (RNA, DNA) cannot go through tight junctions

Metabolic barrier RNA and DNA are degraded by nucleases in endothelial cells and plasma

Large lipophilic drugs are substrates for BBB efflux transporters, which stop the drugs entering the brain.

Chemotherapeutics must overcome two barriers to get to the tumour: the efflux transporters at the BBB and those at the tumour (Brain-tumour barrier). The tumour expresses same efflux transporters as the BBB

56
Q

How can you use nanoparticles in BBB drug delivery?

A
  • Can use nanoparticles (50-100 nm wide, ~10% size of a neuron) to evade metabolic and efflux transport barrier.
  • For delivery of molecules and avoid problems of BBB
  • You encapsulate drug inside particle and it avoids degradation, and efflux transporters cannot detect it
57
Q

What are the advantages of using nanoparticles for BBB drug delivery?

A
  • Can use nanoparticles (50-100 nm wide, ~10% size of a neuron) to evade metabolic and efflux transport barrier.
  • For delivery of molecules and avoid problems of BBB
  • You encapsulate drug inside particle and it avoids degradation, and efflux transporters cannot detect it
58
Q

What are the disadvantages of using nanoparticles for BBB delivery?

A
  • Toxicity of Nanoparticle itself
  • Accumulation of NP in liver and spleen
  • Not targeted to brain (will enter other organs too)
  • Clinical trials needed for both the drug and the nanoparticle itself, makes costly and time consuming.
  • Still too big to pass physical barrier
59
Q

What are nanoparticles mostly made with and what is an advantage of this?

A

PEG improves stability in blood and circulation time

60
Q

What shape of nanoparticles are the easiest to make?

A

Sphere

61
Q

What is the problem with a linear polymer shape for nanoparticles?

A

Drug is attached on the outside- is less successful and flexible

Short rods are rapidly cleared by the liver

62
Q

What can you modify with a nanoparticle?

A

Shape

Size

Charge

Composition (drug it carries0

  • Ligands can enhance NP function
63
Q

What size is best for nanoparticle BBB drug delivery?

A

50-100nm

64
Q

What charge is best for nanoparticle BBB drug delivery?

A

neutral best as they are most likely to be taken up by cells however +ve can be taken up by activated mediated transport

65
Q

What is an disadvantage of using liposomes (type of nanoparticles) in BBB drug delivery?

A

Have a high lipid content and some are getting through the brain however too large to pass through tight junctions

66
Q

What is the only transport mechanism that can deal with the large size of nanoparticles?

A

Transcytosis (receptor mediated, adsorptive)

67
Q

What are trojan drugs?

A

Attach an endogenous molecule to the NP, that the BBB usually transports or recognises.

68
Q

What are the 2 main approaches for trojan drugs?

A
  1. Include an endogenous molecule (the ‘trojan’) on the surface of a nanoparticle, so the BBB takes up the NP + drug cargo
  2. Derive an antibody that binds to a BBB transporter (the ‘trojan’) link the antibody to the NP so it is targeted to the BBB and gets transported – receptor mediated transcytosis

Ligand may not go all the way through but the drug will

69
Q

What did they find when using nanoparticles to deliver Paclitaxel chemo for brain tumours?

A
  • Increases circulation time from 5 hours to 24 hours in mice
  • 50-80 nm in diameter, with the drug enclosed inside the nanoparticle
  • Found a significant decrease in tumour size with nanoparticle and drug compared to drug alone
70
Q

What are two examples of receptors that could be clinically significant for receptor mediated transcytosis?

A
  • Transferrin via iron

* Low density lipoprotein (LDL)-receptor related protein 1 and 2 – lipoproteins

71
Q

How was Nanoparticle Paclitaxel improved?

A

Nanoparticle Paclitaxel using a ligand for LDL-receptor protein 1 receptor mediated transcytosis

  • Attached to the outside of the NP
  • Ligand = Angiopep2
  • Found there was greater accumulation in the brain compared to normal NP drug in mice
72
Q

The receptors used to initiate RMT are not unique to the BBB. True or false?

A

True But the BBB has high levels of transferrin RMT (TfR) & lipoprotein RMT (such as LRP), so these are most often used in brain drug delivery development.

73
Q

How did scientists formulate Temozolomide to cross BBB?

A

Delivering gene therapy via PEG coated NP temozolomide with a ligand for transferrin receptor mediated transcytosis

  • P53 initiator for cell death (apoptosis)
  • Plasmin on the inside upregulates p53
  • Ligand- transferrin antibody
  • Reduces tumour growth
74
Q

What is the novel idea of the nanoparticle taken up by 2 BBB systems?

A
  • A ligand for LRP added
    and they have also tried to make use of the non-specific adsorptive mediated transcytosis. (needs to be of a certain size and have a +ve charge to be taken up by adsorptive mediated transcytosis)
  • The NP has two layers with drug inside (but is not a liposome), layer one, a polymer.
  • Layer 2 is a PEG and the ligand.
  • The two layers are connected by linkers that can be broken down by the BBB’s metabolic enzymes (matrix metallo proteases)
  • In particular, one of the matrix metalloproteases MMPs secreted by tumour cells -excreted extracellularly and allow tumour cells to migrate
  • Endothelial cells also secrete a small amount of MMP 9.
  • MMP removes PEG and changes nanoparticle from -ve to +ve as it exposes the ligand layer à taken up by adsorptive mediated transcytosis
75
Q

What is the novel idea of creating a nanoparticle that actively moves (chemotaxis)?

A
  • If it moves around actively, it is more likely to hit the BBB.
  • A NP that contains enzymes that break down glucose (ultimately to O2) If one side has a weaker wall, O2 should jet out and will move by jet propulsion
  • LDL receptor related protein 1 with Angiopep ligand
76
Q

What are the advantages of nanoparticles in BBB drug delivery?

A
  • Protects drug from plasma clearance and degradation
  • Packages a relatively large volume for drug delivery
  • Carry a wide range of drugs and gene modifiers

NPs can target BBB transport system:

  1. Can use both RMT and AMT – overcomes physical BBB to large molecules
  2. Use vesicular transport systems – overcomes metabolic and efflux transport BBB
  3. Are ultimately taken up by brain – overcomes problem of CSF clearance
77
Q

What are the advantages of antibody based therapies and give examples?

A
  • High specific targeting of a single aspect of the disease process e.g.

o Reducing amalyoids peptide production

o Reducing Tau neurofibrillary tangle formation

o Inhibit neuronal death by apoptosis

o Or glutamate toxicity

o Deliver supporting growth factors

  • Few unwanted effects elsewhere in body (passive immunotherapies -no immune response and especially as it is so specific for a particular area)
  • Antibiodies are large so will be in brain for a long time
78
Q

What are the disadvantages of antibody based therapies?

A
  • Very large molecules (~150,000 Da), very hard to deliver to brain
  • Toxicity- many have been discontinued in clinical trials.

Only one is still active in clinical trials

79
Q

What are 2 ways to improve drug delivery with antibodies?

A
  1. Use an antibody to target an RMT receptor (Trojan) and link to another drug (similar to NP strategy)
  2. Bispecific antibodies. A single antibody, where one light chain can target the BBB (act as the trojan), and the other side has the therapeutic on.
80
Q

Scientists developed human insulin receptor antibodies. What was a disadvantage of these?

A
  • Pancreas and cardiotoxicity and disruption of glucose control throughout the body
  • Glucose depressed 3 hours after infusion
81
Q

In clinical trials, how have bispecific antibodies been used to used to help dementia?

A

Using Transferrin receptors

  • BACE1- enzyme that produces amyloid in the brain via beta secretase
  • Anti-BACE1 antibody inhibits this enzyme from producing amyloid beta
  • So amyloid should decrease in the brain
82
Q

What was a main problem that occurred using antibodies with transferrin?

A
  • Affinity was so high for TfR, most the Ab didn’t leave the receptor on the brain side. (we want enough affinity to get through but not so much it becomes stuck)
  • This issue is largely specific to antibodies because they are capable of very high affinity bonding
  • (→must optimise Ab affinity) -reduce affinity just enough to be released to the brain but not too low to affect BBB targeting which has been shown to work in early clinical trials by looking at inhibition of transferrin
83
Q

What is the rate limiting step for receptor mediated transcytosis?

Which one is of clinical interest and why?

A

Recycling of receptors- rate of re-insertion of receptor

LRP RMT system is of most interest because it is so fast. The receptor can be recycled (take stuff across and move back) 4000 times a day. And can deliver to brain within 30s.

ETMM (5 decks)

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