Neurophysiology 2

Question 1

What are some examples of CNS Disorders?

Answer 1

• Parkinson’s
• Alzheimer’s
• Huntington’s
• stroke
• depression
• chronic pain
• cancer
• dementia
• amyotrophic lateral sclerosis
• multiple sclerosis
• HIV-associated conditions
• epilepsy
• psychoses

Question 2

What is the Blood Brain Barrier? (Function?)

Answer 2

Separates CNS from periphery.

Maintain CNS homeostasis (reduce fluctuations)

Question 3

What is the Blood Brain Barrier composed of?

Answer 3

Vascular network of 300-400 miles in the brain.

Barrier structure composed of endothelial cells (and other cell types)

• Pericytes - associated with endothelial cell
• Astrocytes (star shaped) interact with endothelial cells.

Question 4

What are Tight Junctions?

Answer 4

Protein Cement - seal the gap between adjacent cells.

This makes it difficult for compounds to squeeze through cells and enter the brain.

Question 5

What does Glut1 do?

Answer 5

Glucose Transporter 1.

The brain needs large amounts of glucose transported via Glut1.

Question 6

Why does the brain need complex receptors?

Answer 6

The brain also needs large molecules, therefore cannot use transporters and needs large more complex receptor (e.g. transferrin)

Question 7

What is Receptor Mediated Transcytosis?

Answer 7

Across the BBB is a potential pathway for drug delivery to the brain.
The transfer of molecules across cells from one side to the other.
It binds to receptor on the surface of the cell, crosses the cell and then is released in the brain.

Question 8

How does the BBB protect brain from exposure?

Answer 8

Circulating endogenous chemicals (hormones, NTs) - don’t want these to get into the brain.
Exogenous toxins, pollutants.

Question 9

How does the BBB impact CNS drug delivery?

Answer 9

It can prevent some drugs from getting to the brain.
This is a good thing i.e if you give a patient a neurotoxic drug.
Issue when you want to treat a CNS disease as you need the drug to cross the BBB in order to treat the disease.

Question 10

How do brain capillaries differ from general capillaries?

Answer 10

Brain capillaries, unlike those in most parts of the body, are non-fenestrated, so that drug molecules must traverse the endothelial cells, rather than passing between them, to move from circulating blood to the extracellular space of the brain

Question 11

Is the Brain selective with what enters it?

Answer 11

• Only a limited number of ions are able to squeeze through protein complex and enter the brain, junctions are very selective in terms of what they allow to enter the brain.
• Some small hydrophilic molecules (tight junctions  brain (paracellular – around the cell)
• Other molecules traverse cells (transcellular) – across cells

Question 12

Why is does the BBB cause major problems for drug development and delivery?

Answer 12

Expensive

Extensive Time Scale

Question 13

What causes Parkinson’s Disease?

Answer 13

Loss of neurotransmitter dopamine

Idiopathic - don’t know the cause

Question 14

Why is Parkinson’s Disease not treated with Dopamine?

Answer 14

Not treated with Dopamine because it doesn’t cross the BBB. It is a relatively small molecule but doesn’t have the required physiochemical properties to cross the BBB.

Question 15

How is Parkinson’s Disease treated with?

Answer 15

Use L-Dopa, a modified structure that is picked up by a transporter and crosses into the brain..
Decarboxylating enzyme converts L-Dopa to Dopamine.

Question 16

What are BBB efflux transporters?

Answer 16

Efflux transport at the blood-brain barrier (BBB) limits the brain tissue exposure to a variety of potential therapeutic agents.
They happen constantly and use ATP as an energy supply to pump the molecules out.

They reduce penetration of toxins and therapeutic drugs into the brain.

Question 17

How do BBB efflux transporters work?

Answer 17

As the drug diffuses into the plasma membrane, it can be recognized by the different efflux transporters that pump the drug back into the blood.
E.g. HIV, virus in the CNS,

Question 18

How are Brain Tumours treated?

Answer 18

Chemotherapeutics must reach tumour cells.
Surgery - incredibly invasive.

If drugs are administered PO or IV, ultimately it enters circulation, then it has to cross the BBB.

Problem with these drugs is that they are substrates for efflux transporters.

Limited treatments.

Some drugs administered intrathecally (i.t.)

Question 19

Tell me about Chemotherapy?

Answer 19

Methotrexate (i.t.) and Vincristine (i.v.) Essential that they are administered via these routes.
If these routes are mixed up = neurotoxic, and therefore a Neurosurgical Emergency.

Solution: CSF aspiration (remove), irrigation, i.t., plasma (binds vincristine due to higher levels of protein which is what we need to remove the vincristine)