Stroke: Animal models and developing therapies Flashcards
Overview of animal models for ischaemic stroke?
RODENTS
- Filament MCA occlusion
- Craniotomy: Permanent or Transient MCA occlusion
- Embolic Stroke/Thromboembolic MCA occlusion
- Photothrombosis model
LARGE ANIMALS TOO
Describe and evaluate filament MCAo?
External carotid artery ligated -> advance to proximal MCA -> occlusion
Monitor blood flow
Time to reverse determines infarct size
PROS
- no cranectomy
- reperfusion
CONS
- hypothermia
- weight loss
Describe and evaluate craniotomy model?
For permanent occlusion -> coagulation or ligation
For transient occlusion -> clip or ligation
PROS
- no hypothermia
- long term observation possible
CONS
- skull opened (surgical trauma/dural incision)
- doesn’t model recanalisation
- surgical skill required
Describe and evaluate embolic stroke model?
Catheter inserted into extra-cranial vasculature -> inject pre-produced thrombi
Confirm occlusion w/ laser doppler flowmetry
PROS
- models most common cause of human stroke
- can model recanalisation
- no craniectomy
- no hypothermia
- lower mortality than filament MCAo
CONS
- high variability
- poor control over site of clot lodgement
- surgical skills required
- low success rate
Describe and evaluate photothombosis model?
Rose Bengal is photosensitive -> produces ROS with light
Laser to occlude small vessels in brain
PROS
- very small, precise lesions (precise localised infarction and you can target functionally defined regions)
- high repdroducibility
- dura not opened
- minimal mortality
CONS
- additional direct effects on brain function
- endothelial lesion
- expensive material + difficult method
- useful only for specific study aims
Describe and evaluate large animal models?
Monkey, dogs, cats, pigs, rabbits, sheep
PROS
- closer to human brain anatomy
- similar dimensions to humans
- imaging has better resolution
CONS
- cost
- ethical concerns
- high variability
- different circulatory system (e.g. sheep have more collaterals)
Most important limitation of using rodent brain models for human pathology?
Humans have a gyrencephalic brain, whilst rodents have a thelissencephalic brain
Compare a rodents brain to a human brain
Rodents have:
- increased capillary density
- decreased inter-capillary diffusion distance
- increased CSF turnover
- different grey matter:white matter ratio
What model to use of pre-clinical verification of drug action?
- WT/transgenic
- multiple strains
- multiple models
- comorbidities
Animal study flaws that cause “translational roadblack” between animals and humans?
Animal studies
- used only healthy, young animals
- stat problems, randomisation, blinded analysis, power, sample size
- no clinically relevant time point of treatment
- physiological parameters not controlled
Clinical study flaws that cause “translational roadblack” between animals and humans?
- adequate drug levels not reached
- time window was not used based on preclinical data
- pt inclusion for study didn’t adjust for mode of drug action
- insufficient stat power to prove efficacy
Describe and evaluate the collagenase-injection model?
Bacterial collagenase destroys basal lamina of cerebral blood vessels dose dependently
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bleeding in the surrounding tissue
BUT foreign protein is introduced
Describe and evaluate the blood injection model
Direct injection of blood into the striatum
BUT no vessel damage or trauma
Describe stroke-induced immunodeficiency
[demonstrated in vitro]
Lymphocytopenia, decreased responsiveness of immune cells to in vitro stimulation
Describe the mechanism behind stroke-induced immunodeficiency
Release of stress hormones bind to receptors on immune cells -> immunosuppression
Biphasic: Day 1: massive immune cell upregulation; Day 4: Downregulation and splenic atrophy
