PH2113 - Neuropharmacology 8

Question 1

What is CNT?

Answer 1

Concentrative Nucleoside Transporter

Question 2

What is LAT1?

Answer 2

Large Neutral Amino Acid Transporter 1

Question 3

How many new cases of brain tumours are there in the UK each year?

Answer 3

4,500

Question 4

How many types of brain tumour are there?

Answer 4

> 100 different types

- 50% gliomas

Question 5

What percentage of brain tumours that originate from brain cell lineage (not metastatic) are High Grade Gliomas?

Answer 5

70 - 80%

Question 6

Give examples of types of glioma

Answer 6

Ependymomas
- from ependymal cells lining the ventricles
Oligodendrogliomas
- from oligodendrocytes support and insulate axons
- myelin sheath
Astrocytomas
- from astrocytes
- low grade tumours (1-2)
- generally benign
- high grade tumours (3-4)
- malignant
Grade 4 astrocytomas "gliobastoma multiforme (GBM)
- surgery
- chemotherapy
- radiotherapy

Question 7

What is the survival rate of Gliobastoma Multiforme?

Answer 7

6% survival at 5 years after diagnosis

Question 8

What effect does a tumour near the Blood-Brain Barrier have on the integrity of the barrier?

Answer 8

Tumours > few mm associated with compromised Blood-Brain Barrier structurally and functionally
- Blood-Brain Barrier leakier
Tumour size at diagnosis typically cms

Question 9

Give examples of inflammatory mediators relating to High Grade brain tumours

Answer 9

Tumour necrosis
VEGF
Hypoxia

Question 10

What is the function of inflammatory mediators relating to High Grade brain tumours?

Answer 10

Loss of connection between brain parenchymal cells and brain micro-vascular cells
- increased extracellular space at basal surface of endothelial cells
Down-regulation of tight-junction proteins and increased paracellular permeability
Increased capillary permeability
Induce new tumour blood vessel growth
- angiogenesis
Tortuous, highly disorganised and highly permeable with abnormalities in the endothelial cell wall and basement membrane

Question 11

What is vasogenic oedema?

Answer 11

Disruption of the Blood-Brain Barrier resulting in the formation of a plasma-derived protein-rich exudate
- breakdown in the tight endothelial junctions

Question 12

What can cause vasogenic oedema?

Answer 12

Stroke
High altitude
Brain tumours

Question 13

How is vasogenic oedema produced?

Answer 13

Local production of factors that increase the permeability of tumour vessels, VEGF, TNF and leukotrienes
Increased vascular permeability causes influx of protein-rich fluid and cells by chemotaxis
- monocytes
- macrophages

Question 14

What is vasogenic odema?

Answer 14

Raised interstitial fluid pressure
- ISP/IFP
Reduced perfusion and low pO2
For inoperable tumour medical intervention
- steroid treatment
- dexamethasone
- anti-VEGF antibody
- bevacizumab

Question 15

What is Avastin used to treat?

Answer 15

Used judiciously can partially normalise the tumour vessels

• reduced permeability more like the restrictive Blood-Brain Barrier phenotype
• less leakage of fluid (and drugs) into the tumour interstitium
• reduced ISP (IFP) and improved perfusion
• may increase drug delivery

Question 16

What is convection enhanced drug administration?

Answer 16

Delivers drug directly to the brain through one or more very small tubes which are surgically placed into the brain tumour
Placement of guide tube under surgery with CT/MRI scans
- 1 mm diameter
Catheter remains in place over a 3-4 day course of drug administration (infusion) and then removed
Guide tube remains for further round of treatment as required with a new catheter
Diffusion and convection driven distribution with brain parenchyma to 1-20mm distances from site of administration

Question 17

What is convection-enhnced drug delivery used for?

Answer 17

Inoperable brain tumours

- brain stem gliomas

Question 18

What percentage of strokes are ischaemic?

Answer 18

85%

• impaired blood supply
• lack of oxygen
• lack of glucose
• reduced ATP production
• dysregulation of ion gradients
• cytotoxic oedema

Question 19

What are the features of an acute ischaemic stroke?

Answer 19

Release of toxic molecules
- glutamate
- catalytic enzymes
- generation of ROS progressively damages tissue distal to clot
Blood-Brain Barrier tight junction breakdown
- peak ~4-6 hours post stroke
Blood-Brain Barrier breakdown predisposes to Haemorrhagic Transformation

Question 20

What is the therapy for an ischaemic stroke?

Answer 20

Disintegrate clot

• give recombinant Tissue Plasminogen Activator within 4.5 hours
• 15% of ischaemic strokes receive IV rTPA

Question 21

How does an ischaemic stroke cause damage?

Answer 21

Blood-Brain Barrier breakdown already ongoing

• BBB damage accentuated by reperfusion
• predisposing to haemorrhagic transformation

Question 22

What is haemorrhagic transformation?

Answer 22

Blood leakage into the brain parenchyma
- highest risk of haemorrhagic transformation 24 - 28 hours

Haemorrhagic transformation of cerebral infarction is a potentially infarction is a potentially serious occurance
- < 5% following acute ischaemic stroke

Question 23

What are the main predictors of clinically significant haemorrhagic transformation?

Answer 23

Age
Clinical stroke severity
Blood pressure
Diabetes
Early CT changes

Question 24

What is Multiple Sclerosis?

Answer 24

Non-traumatic neurological disability
- aetiology involves autoimmunity with self-reactive T-cells specific for myelin proteins initiating an inflammatory cascade resulting in neuro-inflammation, demyelination and axonal damage

Question 25

What is Alzheimer’s Disease?

Answer 25

Chronic neurodegenerative disorder
- neuronal degeneration, gliosis, amyloid beta accumulation, plaque and neurofibrillary tangles development
Chronic brain inflammation with microglial cell involvement
Blood-Brain Barrier dysfunction may contribute to onset/progression of Alzheimer’s Disease
- low density lipoprotein receptor related protein 1 (LRP1) transporter in BBB shown experimentally to mediate efflux of amyloid beta from brain and reduced in BBB cells of Alzheimer’s Disease patients
- amyloid beta deposits in the vasculature enhance BBB permeability in the Alzheimer’s Disease brain