NS Fundamentals - Blood Brain Barrier

What did the Goldmann experiment of 1913 discover?

- Trypan Blue intracerebroventricular injection lead to CNS staining but body unstained

- Trypan Blue intravenous injection lead to body staining but CNS unstained

- ultimately discovered the Blood Brain Barrier

Describe the Vascular Supply for the brain.

- Astrocytes form the Blood Brain Barrier

- 2 Carotid (front of neck) and 2 Vertebral (back of neck) Arteries

- Joining of arteries to form the Circle of Willis

- Diverging off into Pial arteries

- Followed by arterioles and finally capillaries

What are characteristics of Capillaries in the Brain?

- The level of complexity in the capillary network of the brain is far greater than normal bodily tissues (no cell is far from capillary)

- Much higher density of capillaries in brain compared to normal bodily tissue (linking to above)

- Form a luminal membrane (barrier closest to capillary) and an abluminal membrane (barrier further out from capillary)

Describe the Vascular component of the Blood Brain Barrier.

- Capillary lumen is surrounded with a single endothelial cell, making up a mono-layer wall

- Paracellular Cleft is region where the endothelial cell joins itself via Tight and Gap (adheren) junctions

Describe the Neural components of the Blood Brain Barrier.

- Endothelial Basement Membrane = separates tissue and protects from mechanical stress

- Astrocytic Basement Membrane = same as above

- Glycocalyx = gel-like substance around cell, providing physical barrier against other substances

- Pericyte = maintain the blood vessels

What are Astrocytic endfeet, and what do they do?

- A projection structure of an astroctye that covers the capillary endothelium, and an astrocytic may have more than one of these, so more than one interaction is possible

- Form Perivascular sheet with endfeet around capillaries

- Form Glia-limitans with endfeet at surface of brain

What are the functions of Astrocytes?

- provide nutrients for neurons

- ion and water homeostasis (expresses high density of aqauporins)

- Terminate synaptic activity

- Maintenance of Blood Brain Barrier

- Breathing regulation via partial pressure detection

What are the different permeation mechanisms between blood and tissues?

- Simple (paracellular) and Passive (transcellular) diffusion

- Transporters influx and efflux (can be expressed in luminal and/or abluminal membranes - endothelium and astrocytes) ("polarised expression" is when transporters are expressed on one membrane and not the other)

- Endocytosis

Describe the composition of the Paracellular Cleft.

- Paracellular movement is mediated by Gap (adheren) and Tight Junctions, found mixed together throughout the paracellular cleft

- Gap junctions and Tight junctions both bind to the actin cytoskeleton on the cell

- Tight junctions prevent movement of ions and molecules between the intracellular space

What are the features of the cerebral capillary endothelium?

- Physical barrier formed via continuous strands of tight junctions at paracellular clefts

- Chemical barrier that is highly selective via high levels of transporters and reduced levels of vesicles or fenestrations

- Metabolic barrier via enzyme systems that metabolise foreign molecules attempting to move between the BBB

How does the BBB act as a physical barrier?

- It has continuous strands of tight junctions, increasing impermeability

- Electrical resistance is significantly higher for brain capillaries, contributing to ion impermeability

- Phospholipid bilayers mean mainly lipophilic molecules are able to pass the BBB

How does the BBB act as a chemical barrier?

- It has a high level of specific transporters, with a reduced level of vesicles and fenestrations

- Transporters found are for substances that are necessary for CNS function such as D-Glucose, or Amino acids

- ABC efflux transporters actively remove foreign substances that attempt to pass the BBB back into the capillary

How does the BBB act as a metabolic barrier?

- It has enzyme systems that metabolise molecules that attempt to enter the brain, and prevent further transport by making them less lipophilic

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What are the functions of the BBB?

- To control the molecule influx into the brain Interstitial Fluid (provides optimal environment for neuronal function)

- To supply the brain with essential materials

- To mediate efflux of waste products

- To restrict ion and fluid movements (protects from ion fluctuations)

Why do drugs need to be able to pass the BBB?

- For treatment or prophylaxis of neurodegenerative conditions (cause degeneration of neuronal matter) or neurological conditions (cause malfunction of neuronal matter)