PH2113 - Neuropharmacology 8 Flashcards
What is CNT?
Concentrative Nucleoside Transporter
What is LAT1?
Large Neutral Amino Acid Transporter 1
How many new cases of brain tumours are there in the UK each year?
4,500
How many types of brain tumour are there?
> 100 different types
- 50% gliomas
What percentage of brain tumours that originate from brain cell lineage (not metastatic) are High Grade Gliomas?
70 - 80%
Give examples of types of glioma
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
What is the survival rate of Gliobastoma Multiforme?
6% survival at 5 years after diagnosis
What effect does a tumour near the Blood-Brain Barrier have on the integrity of the barrier?
Tumours > few mm associated with compromised Blood-Brain Barrier structurally and functionally
- Blood-Brain Barrier leakier
Tumour size at diagnosis typically cms
Give examples of inflammatory mediators relating to High Grade brain tumours
Tumour necrosis
VEGF
Hypoxia
What is the function of inflammatory mediators relating to High Grade brain tumours?
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
What is vasogenic oedema?
Disruption of the Blood-Brain Barrier resulting in the formation of a plasma-derived protein-rich exudate
- breakdown in the tight endothelial junctions
What can cause vasogenic oedema?
Stroke
High altitude
Brain tumours
How is vasogenic oedema produced?
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
What is vasogenic odema?
Raised interstitial fluid pressure - ISP/IFP Reduced perfusion and low pO2 For inoperable tumour medical intervention - steroid treatment - dexamethasone - anti-VEGF antibody - bevacizumab
What is Avastin used to treat?
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
What is convection enhanced drug administration?
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
What is convection-enhnced drug delivery used for?
Inoperable brain tumours
- brain stem gliomas
What percentage of strokes are ischaemic?
85%
- impaired blood supply
- lack of oxygen
- lack of glucose
- reduced ATP production
- dysregulation of ion gradients
- cytotoxic oedema
What are the features of an acute ischaemic stroke?
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
What is the therapy for an ischaemic stroke?
Disintegrate clot
- give recombinant Tissue Plasminogen Activator within 4.5 hours
- 15% of ischaemic strokes receive IV rTPA
How does an ischaemic stroke cause damage?
Blood-Brain Barrier breakdown already ongoing
- BBB damage accentuated by reperfusion
- predisposing to haemorrhagic transformation
What is haemorrhagic transformation?
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
What are the main predictors of clinically significant haemorrhagic transformation?
Age Clinical stroke severity Blood pressure Diabetes Early CT changes
What is Multiple Sclerosis?
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
What is Alzheimer’s Disease?
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
