Blood Brain Barrier

Question 1

Describe the tight junction in the EC of brain blood vessels.

Answer 1

Junction is held tightly with 3 proteins from top to bottom: claudin, JAM (junctional adhesion molecule), and occludin.

Question 2

Describe key features of the BBB.

Answer 2

• EC membranes assymetrical luminal vs abluminal
• Substrates entering brain must cross two membranes and the cytoplasm
• when crossing the cytoplasm may be altered by enzymes

Question 3

What cells are involved in making CSF?

Answer 3

Choroid plexus and transporters. Create osmotic gradient, water comes from ECF/blood into the CSF across the epithelium.

Question 4

What transporters are essential for CSF formation?

Answer 4

Na/K ATPase, NKCC pump, Na+ pump.

Question 5

How can CSF formation be affected by transport inhibitors?

Answer 5

• Acetazolamide: carbonic anhydrase inhibitor
• Ouabain: inhibits Na+/K+ ATPase
• Furosemide: inhibits Na, K+, 2 Cl transporter (NKCC pump)

Question 6

What are the basic transporters for nutrient influx?

Answer 6

1. Paracellular aqueous pathway for water soluble agents. Physiologically fairly irrelevant due to the tight junctions, unless in pathological state.
2. Transcellular lipophilic pathway. Alcohol, heroine, and cocaine utilizes this pathway.
3. Transport proteins. Get’s the nutrients into cell. Ex. MCT1 ships lactate in and out of brain. Expression of this protein is much higher in suckling rats and adults on ketogenic diet.

Question 7

What are the major transporters for efflux of drugs?

Answer 7

P-glycoprotein (Police) aka Mdr1a/b. Protective mechanism of toxic things that might be in our diet. Also sends out therapeutic drugs.
Bcrp1 is also a drug efflux transporter.

Question 8

When and how is the BBB/NVU formed?

Answer 8

First few weeks of fertilization. Neuroepithelial cells secrete Wnt7a/7b, vascular EC respond, enter the neuroepithelium, and express GLUT1.

Question 9

What are some diseases linked to the dysfunction of the NVU?

Answer 9

*When the endothelial cell is dysfunctional, then the cells around it are dysfunctional resulting in a neurological disease. MS, Alzheimers, Epilepsy, etc. many diseases.

Question 10

What is the Trojan Horse model for drug delivery to the CNS?

Answer 10

Chemically bind paclitaxel compound to LRP-1, which is carried into the brain via transcytosis. Thus, paclitaxel hitches a ride in on LRP-1.

Question 11

How do cells of the immune system get into the brain?

Answer 11

Diapediesis: rolling (weak adhesion), emigration (strong adhesion), slipping through the cracks. INcreased in MS, stroke, traumatic injury, others.