Stroke: Animal models and developing therapies Flashcards Preview

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Flashcards in Stroke: Animal models and developing therapies Deck (19)
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1

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

2

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

3

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

4

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

5

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

6

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)

7

Most important limitation of using rodent brain models for human pathology?

Humans have a gyrencephalic brain, whilst rodents have a thelissencephalic brain

8

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

9

What model to use of pre-clinical verification of drug action?

- WT/transgenic
- multiple strains
- multiple models
- comorbidities

10

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

11

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

12

Describe and evaluate the collagenase-injection model?

Bacterial collagenase destroys basal lamina of cerebral blood vessels dose dependently
|
bleeding in the surrounding tissue

BUT foreign protein is introduced

13

Describe and evaluate the blood injection model

Direct injection of blood into the striatum

BUT no vessel damage or trauma

14

Describe stroke-induced immunodeficiency

[demonstrated in vitro]
Lymphocytopenia, decreased responsiveness of immune cells to in vitro stimulation

15

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

16

Relationship between infarct size and stroke-induced immunodeficiency?

Greater infarct size -> greater immunosuppression -> more infections

NB: pneumonia is main cause of death

17

Acute ischaemia regarding stroke-induced immunodeficiency?

Acute ischaemia -> acute inflammation -> infarct enlargement

18

Mechanism behind acute ischaemia causing infarct enlargement

Microglial activation -> pro-inflammatory cytokines -> more adhesion molecules/chemokines -> more transmigration

19

Role of Natalizumab in stroke-induced immunodeficiency?

Blocks integrin a-4 on T cells -> reduced VCAM-1 and VLA-4 interaction -> reduced transmigration of adhesion molecules/chemokines