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Blood Brain Barrier - MPharm 4 > BBB L1 - 2 > Flashcards

BBB L1 - 2 Flashcards

1
Q

Why is drug delivery to the brain an issue for the pharma industry?

A
  • failure in treating neurodegenerative diseases e.g. AD, PD, dementia, and brain tumours e.g. Gliomas
  • <5% drugs in trials show clinical benefit - don’t cross BBB
  • Cost of failed trials = puts of pharma trying
  • don’t give pt false hope
  • complex to develop e.g. animal models different metabolic systems
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2
Q

Why does a barrier exist between the brain and the blood?

What is the need for homeostasis of brain ECF?

A
  • separate blood from brain ECF

- shield from composition of blood e.g. glutamic acid = toxic and causes apoptosis

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3
Q

What does Brain ECF include?

A

1) Brain tissues interstitial fluid (ISF) = between neurones and capillaries
2) Ventricular cerebrospinal fluid (CSF)

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4
Q

What experiment shows evidence for the existence of the BBB?

A
  • Goldmann Trypan Blue
  • IV = only body stained
  • IT (Intrathecal) = only CNS
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5
Q

1) Why is there need for a barrier - 5 reasons

A

1) Ion regulation - need optimal Na and K conc for optimal neuronal signalling
2) Molecular traffic: Keep toxins out = low cell death
3) Low protein - proteins = cell division and brain is surrounded by fixed skull
4) Preserve neurotransmitter signalling = separate CNS:PNS
5) ‘Silent’ immune surveillance. Keep leukocytes out to limit inflammation -brain has its own immune cells - microglia

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6
Q

What are three key Clinical Significance points for homeostasis of brain ECF?

A

1) K+ equilibrium potential = approx. -100 mV –> reduce seizures, action potentials specific, acidity = faster repolarisation
2) Low protein = reduce water retention and brain oedema
3) Low Ca and glutamate = reduce potential excitotoxicity and subsequent neurodegeneration

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7
Q

Sites of brain barriers

A

BBB = capillaries

Blood-CSF- barrier = choroid plexuses

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8
Q

Stats about brain energy usage and size of anatomy

A

•Brain has high energy requirement:
•uses ̴ 15% of glucose and O2 but is only 2% of body weight.
•Rich capillary network needed for constant supply of nutrients - similar to exercising muscle- to keep neurones active and Na/K pump operational.
- The brain used 7x more glucose and oxygen than non exercising muscle = need for dense capillaries.
- Human brain – 1500 g
- Capillary total length – 600km
- Surface area – 20 m2
- Capillary volume -17 mL of blood
- Inter-capillary distance - 40um
- Capillary lumen diameter – 7 um – only fits one RBC
- Length per neurone – 10 um

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9
Q

What are the three components that form the BBB?

A

1) Physical
2) Transport
3) Metabolic

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10
Q

1) Physical Barrier

  • what cells overlap and what protein junction forms between them?
  • what type of brain cell secrete the factors secrete factors to make the said junctions?
A
  • Endothelial cells
  • Tight Junctions
  • Astrocyte secrete factors that induce tight junction formation
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11
Q

What is the difference between adherens and tight junctions?

A

Adherens = formed with cadherin, and are in the body

Tight Junctions = complex protein structure in the brain - made up of occludin, claudio, zonnula occludens (ZO)

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12
Q

What unit is used to measure tightness?

A

Ohms cm^2

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13
Q

What is the different resistances between muscle capillary, choroid plexus, and brain capillary?

A
  • Muscle capillary = 40 ohms cm^2
  • Choroid plexus = 200 ohms cm^2
  • Brain capillary = 8000 ohms cm^2 (hence a lot tighter than the rest of the body)
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14
Q

What type of molecules can pass through the BBB?

N.B what certain characteristics do they need to have>

A
  • <400 Da
  • log P >1
  • small
  • lipid soluble

oxygen, nicotine, caffeine, barbiturates, spice, opiates, anaesthetics, alcohol

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15
Q

B) Transport Barrier

  • What are the THREE examples of efflux transporters
A

1) P-glycoprotein
2) BCRP (Breast Cancer Resistant Protein)
3) MRP (Multi-drug Resistance Protein)

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16
Q

What are examples of molecules that the transport barrier for the BBB aims to keep out?

A
  • lipid soluble toxins
  • drugs e.g. chemotherapy, antivirals, antibiotics
  • pesticides
  • plasma amyloid peptide
  • glutamic acid
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17
Q

C) Metabolic Barrier

  • What enzymes are known to exist within the metabolic barrier for the BBB?
A
  • CYP450 of neurones
  • CYP1B1, CYP2U1 - in endothelia
  • CYP2J2, CYP2U1 - astrocyte end-foot
  • CYP2E1, CYP1A1, CYP2C9= rest of astrocyte cell
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18
Q

What type of metabolism to CYP enzymes carry out?

A
  • metabolize vast array of compounds

- drugs, neurotoxins, neurotransmitters, neurosteroids

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19
Q

3) How to things get into the brain?

A

Uptake Transporters - on apical blood-facing membrane

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20
Q

How is a cell described that only allows uni-directional flow?

A

Polarised

  • movement in one direction from the blood-facing membrane
21
Q

What are the key examples and their respective substrates for transporters at the BBB?

A

GLUT1 - Glucose

Mct1 - Lactate (Monocarboxylate)

Lat1 - Leucine (neutral aa)

TfR - Transferrin - important for iron homeostasis

N.B THESE TRANSPORTERS ARE SPECIFIC - ALLOWS TIGHT CONTROL OF MOLECULES CROSSING THE BBB

22
Q

What drug takes advantage of carrier-mediated uptake of aa?

A

L-dopa (Treatment for PD)

23
Q

What are the two types of vesicular mediated transport?

A

RMT - receptor mediated transcytosis - where the system is dependent on the molecule/substrate binding

AMT - aDsorptive mediated transcytosis - where the system is dependent on the substrate acquiring a positive charge

24
Q

4) The Neurovascular unit

- What are the main four cells that make up the neuromuscular unit?

A
  • endothelia
  • neuron
  • astrocyte
  • pericyte
25
Q

What is the action of the astrocyte at the neurones, and relate this to the subsequent effect this has on pericytes - and the end result of this pathway i.e. how does the pericyte act alike smooth muscle and what is the purpose for this?

A
  • astrocyte acts at neurone = has the same receptor as post-synaptic neuronal membrane
  • when Ca2+ released more = increased firing = astrocyte detects this = releases vasoactive compounds to deliver more blood to working neuron
  • astrocyte feedback to pericyte = has myosin and actin = alike smooth muscle by being able to relax and cause vasodilation of capillaries - allowing more blood to be delivered to the neurones
  • if the pericyte contracts i.e. when the astrocyte signals the neurone is less active - the pericyte can contract and restrict blood supply bu causing vasoconstriction.
26
Q

Why is the pericyte control of BBB capillary network of clinical significance in treating neurodegenerative diseases?

A

As neurodegenerative diseases progress - the neurones become less active - hence the pericyte causes vasoconstriction - hence decreased blood supply to these areas.

This is bad as the further the disease progresses - the harder it is to deliver drugs to these sites.

27
Q

How can the blood-flow in the brain be measured to identify neurodegenerative disease?

A

MRI - monitor brain neuronal activity.

Reduced blood flow = disease

28
Q

5) CSF - Cerebrospinal Fluid

- What is the pharmacological significance of the CSF?

A

Removal of Drugs

want to control removal of CSF - i.e. if want to retain drug in the brain

29
Q

What is the name of the anatomy that produces CSF?

A
  • Choroid plexuses of the lateral, third, and fourth ventricles
30
Q

What forms the Blood-CSF-Barrier, and How does it form its barrier?

A

Choroid plexus has capillary surrounded by epithelium - leaky BUT has tight junctions - this is the barrier

N.B the capillaries here are alike normal body capillaries i.e. not BBB - hence can allow molecules in and out freely but it is the tight junctions of the epithelia that form the barrier here.

31
Q

What is the function of these epithelia in the B-CSF barrier?

A

Remove toxins, large molecules e.g. proteins, from the CSF

‘Kidney-like function’

32
Q

What are the similarities between BBB and BCSFC?

A
  • physical barrier (BUT not as tight junctions as BBB)
  • Transport barrier
  • Ion homeostasis = needed for optimal signalling (especially K, Ca2+, Mg2+)
33
Q

What are the 5 ‘extra’ functions of the B-CSF-B?

A

1) Produce CSF
2) Buoyancy (1400g –> 50g)
3) Nutrition (Vit.C, aa, glucose)
4) Excretion/drainage - i.e. acts alike lymphatic system
5) Hormonal secretion e.g. IGF (insulin-like growth factor), Leptin

34
Q

How does the CSF by choroid plexuses occur? What membrane protein complex is influential in this?

A

Na/K ATPase sets up gradient on apical membrane

Causes Na and Cl to move from blood side to CSF side = water follows down osmotic gradient

Water also moves via aquaporins

35
Q

What are the figures relating to:

1) Secretion volume
2) Pressure
3) Volume
4) Composition

A

1) 0.5 mL/min
2) 10 mmHg (ISF = 3 mmHg)
3) 150 mL (Ventricles = 35 mL) - replenished 4 x daily = 600 mL daily.
4) similar to plasma BUT lower protein, glucose, aa and also small but significant differences in K and Ca i.e. less of these

36
Q

Describe

1) The flow pathway, and
2) The drainage of the CSF

A

1) Flow from ventricles, where some to spinal cord, but then makes its way back up and resides mainly over the SUB-ARACHNOID SPACE - the space between brain and the arachnoid membrane
CSF flows between this

2) CSF drains into VENOUS SINUSES - large vein down the centre of the brain - major route for clearance of metabolites/waste/toxins from the whole brain

37
Q

How does the venous sinus allow one-way flow? How does this allow adaptation to increased CSF flow?

A

Has a valve system = allows push of fluid, hence one-way valve allows management of increased CSF flow by pushing the fluid straight into the blood, not allowing any back-pressure

38
Q

What is the perivascular route?

2 ‘spaces’

A
  • Virchow-Robin space (VRS)

- Peri-arterial space (PAS) in human brain

39
Q

How does the CSF move between the perivascular route?

A

Flows back and forth from VRS and PAS

Only flows small-distance

40
Q

The CSF can transverse the brain tissue by the perivascular route, true or false?

A

FALSE

it only travels a small distance in and out of the VRS and PAS spaces

41
Q

What function can the perivascular route play?

A
  • Washing motion - washing out these areas for removal of drugs and,

to aid mobility of drugs across membranes e.g. if high conc. build-up in PAS - the flowing action can spread the drug depot over larger area = aids mobility across the membrane

42
Q

What does the description of a ‘pulsatile movement’ mean with regards to the flow of CSF via the perivascular route

A

it flows back and forth

43
Q

What does the direction of CSF flow via the perivascular route rely on?

A

Fluid pressure i.e. how much CSF and ISF there is

Drug/metabolite concentration

44
Q

What would the interruption of CSF flow cause?

What is non-communicating and communicating?

A

Hydrocephalus: dilated ventricles, swelling of brain, increased intra-cranial pressure = squeezing of brain against the cranium  cause damage.
Non-communicating = usually due to blockage of the aqueduct of Sylviu  results from closure before birth (congenital), of from brain tumour at any age.
Communicating = blockage of CSF flow in sub-arachnoid space or villi
Treatment: shunt of excess fluid in ventricles e.g. to abdominal cavity

45
Q

Why is the flow pulsatile?

A

Aids clearance varies with cardiac cycle, causes movement of CSF back and forth, midnight 42mL/h due to increased BP and minimal at midday 8mL/h. So best to give drug in the day =cleared less

46
Q

How can clearance from the CSF be decreased by pulsatile movement?

A

larger sized drug molecule, but issue with cross BBB initially, can bind to glia cell so is retained for longer

47
Q

Can you break the BBB barrier, When would you do this?

A

This occurs in neurological conditions eg alzheimers where there is break down of BBB this lets in toxins eg glutamate - therefore this technique should only be used to prolong life =FOR END OF LIFE

48
Q

what is a cause of BBB breakdown

A

Traumatic brain injury, stroke, MS, bacterial meningitis’s, epilepsy

49
Q

what is a consequence of BBB

A

alzheimers, epilepsy, HIV related dementia, cerebral malaria, depression, schizo, age-related, parkinson’s disease

Blood Brain Barrier - MPharm 4 (3 decks)

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