BBB

Question 1

What structural components constitute the BBB?

Answer 1

• Glycocalyx covers the lining
• Endothelial cells
• Pericytes
• Astrocyte endfeet
• Basement membrane
• Axon terminals

Question 2

What is the function of pericytes in the BBB?

Answer 2

Vessel stabilization, inhibit endothelial cell proliferation, induction of TJ formation and basement membrane production

Question 3

What is the function of astrocytes in the BBB?

Answer 3

Modulate development and maintenance of the BBB, and support endothelial cells, promote TJ formation

Question 4

What is the function of neurons in the BBB?

Answer 4

Modulate BBB development, and might influence BBB permeability, promote TJ formation

Question 5

What is the function of endothelium in the BBB?

Answer 5

It’s the principle component of the BBB

Question 6

What is the function of basement membrane in the BBB?

Answer 6

Stabilize cellular BBB, promote expression of endothelial TJ proteins

Question 7

Where in the vascular tree is the BBB?

Answer 7

Formed at all parenchymal vessels

Question 8

What is selective permeability essential for, and what is it maintained by?

Answer 8

Essential to sustain brain function, maintained by anatomical features, and specialized transport mechanisms

Question 9

What is the bottleneck of transport across the BBB?

Answer 9

The endothelium

Question 10

Describe the junctional complexes of the BBB.

Answer 10

• between endothelial cells
• limits brain-to-blood diffusion
• more restricted than in the periphery

Question 11

What are the two types of junctional complexes in the BBB, and how do they differ?

Answer 11

Tight junctions: physical barrier
Adherens junctions: cell contact sites stabilization

Question 12

Desrice the paracellular route through the BBB.

Answer 12

Between adjoining endothelial cells: diffusion
- limited to small, water-soluble molecules
- restricted by junctional complexes

Question 13

Describe the transcellular route through the BBB.

Answer 13

Diffusion across the endothelial cells –> sensitive to efflux pumps (shuttle substances back to the blood)
- small lipophilic molecules and gasses

Question 14

Describe the carrier mediated route through the BBB.

Answer 14

Aka. augmented diffusion
–> shuttling molecules across the cell lipid membrane
- Blood –> brain: nutrients
- Brain –> blood: metabolite clearance, NT scavenging
- main route for ion transport across BBB

Question 15

Describe the adsorptive-mediated transcytosis route through the BBB.

Answer 15

• Vesicular transport
• Based on charge of molecule (non-specific)
• Bi-directional
• Suppressed in the brain compared to other tissue
• Key molecules transported: albumin, histone and avidin

Question 16

Describe the receptor-mediated transcytosis route through the BBB.

Answer 16

• Vesicular transport
• Based on receptor-ligand interaction (Very specific)
• Bi-directional, depending on the ferrying receptor
• Clathrin dependent
• Molecules transported: amyloid-beta, leptin and vira

Question 17

Describe the intracellular sorting.

Answer 17

Endocytosis –> sorting in early endosome –> exocytosis/degradation/recycling

Question 18

What is an important drug delivering strategy?

Answer 18

Avoid degradation

Question 19

What is the function of glycocalyx in the BBB?

Answer 19

Enzymatic barrier (toxin degradation), regulate cell adhesion

Question 20

What are the general dysfunctional properties of the BBB in ageing and disease?

Answer 20

Increase of paracellular permeability (TJs loosen) and AMT (more non-selective transport), and decrease of RMT (less selective transport)

Question 21

Why is the BBB so tight?

Answer 21

The brain must keep a constant level of Na and K for optimal neuronal activity, and a constant volume, and xenobiotics and endogenous signaling molecules from the blood should be kept out of the brain

Question 22

How does most CNS drugs pass the BBB?

Answer 22

By passive transcellular diffusion

Question 23

What type of molecules are the vast majority of CNS drugs?

Answer 23

Small, lipophilic molecules with properties favouring passive membrane permeability

Question 24

What is Lat1?

Answer 24

Aka. large neutral amino acid transporter 1:
- antiporter - exchanges an intracellular amino acid for an extracellular one
- target transporter for CNS drugs

Question 25

What are some other target transporters for CNS drugs?

Answer 25

MCT1 and organic cation transporters (oxy, morphine)