BBB Flashcards
What structural components constitute the BBB?
- Glycocalyx covers the lining
- Endothelial cells
- Pericytes
- Astrocyte endfeet
- Basement membrane
- Axon terminals
What is the function of pericytes in the BBB?
Vessel stabilization, inhibit endothelial cell proliferation, induction of TJ formation and basement membrane production
What is the function of astrocytes in the BBB?
Modulate development and maintenance of the BBB, and support endothelial cells, promote TJ formation
What is the function of neurons in the BBB?
Modulate BBB development, and might influence BBB permeability, promote TJ formation
What is the function of endothelium in the BBB?
It’s the principle component of the BBB
What is the function of basement membrane in the BBB?
Stabilize cellular BBB, promote expression of endothelial TJ proteins
Where in the vascular tree is the BBB?
Formed at all parenchymal vessels
What is selective permeability essential for, and what is it maintained by?
Essential to sustain brain function, maintained by anatomical features, and specialized transport mechanisms
What is the bottleneck of transport across the BBB?
The endothelium
Describe the junctional complexes of the BBB.
- between endothelial cells
- limits brain-to-blood diffusion
- more restricted than in the periphery
What are the two types of junctional complexes in the BBB, and how do they differ?
Tight junctions: physical barrier
Adherens junctions: cell contact sites stabilization
Desrice the paracellular route through the BBB.
Between adjoining endothelial cells: diffusion
- limited to small, water-soluble molecules
- restricted by junctional complexes
Describe the transcellular route through the BBB.
Diffusion across the endothelial cells –> sensitive to efflux pumps (shuttle substances back to the blood)
- small lipophilic molecules and gasses
Describe the carrier mediated route through the BBB.
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
Describe the adsorptive-mediated transcytosis route through the BBB.
- 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
Describe the receptor-mediated transcytosis route through the BBB.
- 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
Describe the intracellular sorting.
Endocytosis –> sorting in early endosome –> exocytosis/degradation/recycling
What is an important drug delivering strategy?
Avoid degradation
What is the function of glycocalyx in the BBB?
Enzymatic barrier (toxin degradation), regulate cell adhesion
What are the general dysfunctional properties of the BBB in ageing and disease?
Increase of paracellular permeability (TJs loosen) and AMT (more non-selective transport), and decrease of RMT (less selective transport)
Why is the BBB so tight?
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
How does most CNS drugs pass the BBB?
By passive transcellular diffusion
What type of molecules are the vast majority of CNS drugs?
Small, lipophilic molecules with properties favouring passive membrane permeability
What is Lat1?
Aka. large neutral amino acid transporter 1:
- antiporter - exchanges an intracellular amino acid for an extracellular one
- target transporter for CNS drugs
What are some other target transporters for CNS drugs?
MCT1 and organic cation transporters (oxy, morphine)
