Neurophysiology - Blood Brain Barrier

Question 1

Describe the functions of the blood brain barrier

Answer 1

1. Maintain a constant extracellular environment (e.g. exercise –> changes in pH and K+ that depress neuronal activity) Plasma separated from brain CSF by BBB
2. Protect brain from harmful neuroactive blood-borne substances
3. Prevent CNS neurotransmitters entering systemic circulation

Question 2

What are the anatomical layers of the blood brain barrier

Answer 2

1. Capillary endothelial cells
   Differ from axtracerebral capillaries:
   - Tight junctions
   - High mitochondria content
2. Thick basement membrane
3. Astrocyte foot processes (podocytes)
   - Supportive glial cell
   - Closely applied to endothelial cells

These three layers form a virtually impenetrable layer to lipophobic molecules, comparable to a continuous capillary

Question 3

How do substances cross the BBB

Answer 3

1. Simple diffusion (lipophilic)
   - CO2 / O2 / Steroid hormones / ethanol
2. Active transport
   - Na / K / Mg / Ca / Cl / HCO3 / H
3. Facilitated diffusion (conc gradient)
   - GLUT 1 - Glucose (no ATP and no insulin required)
   - Aquaporins - Water
4. Pinocytosis
   - e.g. Insulin

Question 4

Which substances should be prevented from crossing the BBB

Answer 4

Catecholamines
- Are neurotransmitters

Amino acids
- Also act as neurotransmitters (Glycine and glutamic acid)

Ammonia (NH3)
- Small lipophilic molecule that is potentially neurotoxic –> rapidly metabolized by astrocytes to glutamine and does not normally reach the neurons in significant concentrations

Question 5

Can Dopamine cross the blood barrier. Discuss treatment of Parkinson’s disease

Answer 5

Dopamine cannot cross the BBB.

But its precursor L-dihydroxyphenylalanine L - DOPA is transported by facilitated diffusion.

Parkinson’s disease = dopamine deficiency in the substantia nigra. L-DOPA (levodopa / carbidopa) rather than dopamine is administered as it does cross BBB.

Question 6

Give examples of drugs that cross the blood brain barrier by simple diffusion

Answer 6

Lipid soluble agents:
Propofol
Thiopentone
Volatile anaesthetics
Benzodiazepines

Phenytoin

Question 7

How can drugs by bypass the BBB to reach the CNS

Answer 7

1. Directly: E.g. intrathecal methotrexate / polymer bound chemotherapy agents
2. Meningitis - antibiotics can penetrate an inflamed weakened BBB
3. L-DOPA (shared neutral amino acid transporter –> facilitated diffusion)
4. Increasing the lipophilicity of drugs e.g. diamorphine –> 100 times more lipid soluble than morphine
5. Disrupt BBB with intracarotid mannitol

Question 8

Why is it important that the brain retains a direct connection with the systemic circulation

Answer 8

1. Detection in alterations in composition of blood

2. Secretion of hormones

Question 9

Which central nervous system structures are located outside the BBB?

Answer 9

The ‘circumventricular’ organs - around 3rd ventricle
- Capillaries are fenestrated and therefore they lie outside the blood brain barrier

1. Area postrema (CTZ, post. medulla)
2. Hypothalamus (osmoreceptors)
3. Anterior and Posterior Pituitary (8 hormones 6 + 2)
4. Pineal gland (melatonin)
5. Choroid plexus (uses plasma to make CSF)

Question 10

How is the brain protected despite the breach of BBB at the circumventricular organs

Answer 10

The Blood - CSF barrier remains intact

Hence, substances can leak out of the capillaries into the circumventricular organs, but are unable to enter the CSF and access the brains neurons