Blood Brain Barrier 2: CSF Flashcards
What is MCT1?
Monocarboxylate Transporter-1
A transporter between the blood and endothelium in the blood-brain barrier. It transports things like lactic acid, lactate, pyruvate, acetate, butyrate and ketone bodies.
It is utilized most during exercise, hypoglycemia, fasting and ketogenic diet
How much MCT1 expression is there in the brain of infants?
25% more than in adults. But with a ketogenic diet, even adult MCT1 levels will go up.
What is P-glycoprotein?
It transports drugs outside of the blood side or brain side and pumps them into the blood. It is one of several efflux transporters that keeps drugs out of the brain.
What are efflux transporters important?
If we can modify them somehow, we may be able to improve drug delivery. If you remove the P-glycoprotein in lab exp. you get an inc. of drug in the brain and if you remove it and another efflux transporter you get an even bigger increase.
What is his working hypothesis about blood brain barrier diseases?
When the endothelial cell is dysfunctional, then the cells around it are dysfunctional, resulting in neurological disease.
- MS
- Alzheimer’s
- Glucose transporter dysfunction (de vivo disease)
- Creatine transporter defect
- Meningitis
- Pathogenic infections (bacterial - E. coli, Citrobacter, Parasitic - tryp. Lyme, Plasmodium sp.)
- Viral infections (HIV, others)
- Late-stage neurological trypanosomiasis (sleeping sickness)
- Progressive multifocal leukoencephalopathy (PML)
- Rabies
Blood-brain barrier Diseases/Dysfunctions
What is the LRP transporter?
A good receptor for transporting chemo and other drugs since it can transport large materials quickly. It binds the drug and moves to the other side of the cell, releasing the drug into the brain. If you can design a drug to bind to the receptor, it would be transported across.
What happens if we directly inject a drug into the brain?
It will quickly be pumped out by efflux pumps.
What is the “Trojan Horse” approach?
At some companies (angiochem, genentech, wm. partridge, UCLA) Paclitaxel was bound to a substance that binds LRP receptor well. Then paclitaxel (a good chemotherapy agent- one of the most toxic things for killing tumors) can be targeted to brain tumors. This was used to greatly reduce a side of a woman’s brain lesions.
What is the way cells can get through the blood brain barrier?
Diapedesis
What is Diapedesis?
Immune cell migration from blood into the tissue.
- Lymphocyte rolls, then weakly adheres/sticks
- Then additional/strong adhesion
- Then lymphocyte emigrates/migrates across the cell or tight junction (endothelial cells)
- Chemokines can enhance these actions during an immune response (MS, stroke, trauma, etc.)
What is the medical relevance of leukocyte trafficking into the brain?
- Multiple Sclerosis (autoimmune disease- killing of myelin)
- Cells could be used for brain cancer immunotherapy if the cells could be trained to target the tumor - could be great brain cancer immunotherapy
When does the BBB develop in mice and humans?
11-12 days in mouse & during the first few weeks of development in humans
What is the importance of the Choroid plexus?
It produces CSF and is found in the ventricular system (ventricles) - specifically the epithelial cells of the plexus makes the CSF
What is the brain-CSF barrier made up of?
It is the epithelial cells of the choroid plexus. The formation of CSF is driven by osmosis. Transporters are helpful in driving the osmotic flow and making CSF. We make about 1/3 of our urine volume in CSF everyday.
