Nueurophysiology 2

Question 1

what are 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 function of the blood brain barrier?

Answer 2

• The function of the structure is to separate the CNS from the peripheral circulation. The network of blood vessels which make up the blood brain barrier they would be in the average human 300-400 miles long, huge network that supplies the brain.
• The main function of the blood brain barrier is to maintain CNS homeostasis, the environment of the brain and the spinal cord, needs to be kept a tight regulation on this.

Question 3

what is the blood brain barrier formed of?

Answer 3

endothelial cells, which are specialised for tight control

- also made up or pericytes and astrocytes

Question 4

what are astrocytes?

Answer 4

star shape cells which extend out and the end of these interact with the endothelial cells

Question 5

what are tight junctions?

Answer 5

these are protein cement and sit along the adjacent cells and seal the gap, locking the cells together. This makes it hard for molecules to squeeze through and get into the brain.

Question 6

what transports glucose within the brain?

Answer 6

GLUT1 transporters

Question 7

how does insulin get into the brain?

Answer 7

o The insulin binds to an insulin receptor which allows it to pass through the blood brain barrier.

The molecules binds to the receptor on the cell membrane, it then gets into the endothelial cells and is transcytoses out into the brain. This is receptor mediated.
This is for the larger molecules they are needed to be passed through the cell from transporters on the membranes.

Question 8

how does iron get into the brain?

Answer 8

o Iron is a cofactor for many reactions within the brain, so it binds to transferrin receptor on the cell membrane and gets into the blood brain barrier

Question 9

what can pass through a tight junction?

Answer 9

• Some small hydrophilic molecules can pass through the tight junctions and into the brain (paracellular route – around the cell)

Question 10

what is the function of the blood brain barrier?

Answer 10

The tight junctions are crucial to the structure of the blood brain barrier to make it restrictive.

Question 11

why is the blood brain barrier an issue?

Answer 11

The blood brain barrier is a major problem in terms of drug development and drug delivery. It makes it very expensive for the pharmaceutical companies to produce (few hundred million). The time scale is also much longer then normal drugs.

Question 12

why is direct dopamine not an option for parkinsons disease?

Answer 12

• Treatment of direct dopamine to patients with this disease are NOT used because it isn’t able to cross the blood brain barrier
• Dopamine is relatively small molecule but doesn’t have the right physiochemical properties to be able to cross the blood brain barrier.

Question 13

what is the main treatment of Parkinson’s disease?

Answer 13

• One of the main treatments for this disease would be L-DOPA, which is a modified version taken into the endothelial cells by amino acid transporters

Question 14

what happens when L-Dopa gets into the brain?

Answer 14

• When L-DOPA gets into the brain there is an aromatic amino acid decarboxylase which converts it to dopamine to be used within the brain.

Question 15

what else do endothelial cells in the BBB exxpress?

Answer 15

drug efflux transporters which sit on the membrane facing the blood,.

Question 16

what do drug efflux transporters do?

Answer 16

as a drug or a toxin diffuses into the membrane then the transporters grabs it and then effluxes it back into the blood. This is an active process which is constantly happening and uses ATP as an energy supply. These transporters are functioning to reduce penetration of toxins and drug molecules into the brain.

Question 17

what is a type of treatment for brain tumours?

Answer 17

• One way to treat a tumour is to have surgery, this is very invasive as you need to cut into the skull and then you can place the drug into the brain.

Question 18

what are major routes of admin for treatment of a brain tumour?

Answer 18

• Major routes of drug delivery is orally or iv – this means it gets into circulation and therefore it has to cross the blood brain barrier

Question 19

what is the major problem for drugs in treatment in brain tumour?

Answer 19

• The problem with this is many of them are picked up by the efflux transporters and removed back into the blood, impacting delivery of anti-cancer drugs into the brain.
• This gives them limited treatments due to this

Question 20

what are examples of anti-cancers for brain tumours?

Answer 20

• Doxorubicin
• Vinblastine
• Vincristine
• Methotrexate
• All P-glycoprotein substrates! – this is an issue as they will be effluxed out. The transporters treaa them in the same way as toxins and are pumped out.

Question 21

what is chemotherapy?

Answer 21

• In this type of treatment methotrexate is given (i/t) and vincristine is given (i/v). essential they are given by these routes.

Question 22

why is vincristine no longer given?

Answer 22

• In the past there has been mix up with the drugs and vincristine was given i/t, and this is a potent neurotoxic drug – this causes huge issue. Injected through the spine with a neurotoxic drug.
• This leads to a neurosurgical emergency and it is very difficult to rectify. The approach that is taken is to try to removal the cerebral spinal fluid as it contains the neurotoxic drug, then irrigate the patient and deliver plasma into the spinal (i/t).
• When you give plasma it has higher levels of plasma proteins, which can bind to the vincristine so it will now longer have an affect