Animal Models of Stroke Flashcards
Discuss the advantages and limitations of frequently used animal models of ischaemic and haemorrhagic stroke Address how translational models of stroke can be used to establish new therapeutic avenues focusing on immunomodulatory mechanisms
Name the three main uses of animal models
Studying pathophysiology, validating clinical observations, and drug development
Name 3 models of focal cerebral ischaemia
Proximal middle cerebral artery occlusion, distal middle cerebral artery occlusion, thromboembolic middle cerebral artery occlusion, endothelin model, photothrombosis model
Name 2 animal models of global cerebral ischaemia
Four vessel occlusion, two vessel occlusion, cardiac arrest and resuscitation
Describe the filament middle cerebral artery occlusion model (filament MCAo)
A filament is inserted to occlude the coronal carotid artery and the origin of the middle cerebral artery temporarily - typically for 45-90 minutes
Give 3 advantages of the filament MCAo model
Relatively easy operation, no craniectomy required, can assess reperfusion
Give 3 disadvantages of the filament MCAo model
Hypothermia, weight loss, high mortality, short observation period, high degree of variability
Name 2 surgical models of transient MCA occlusion, and 2 models of permanent occlusion
Transient: MCA clipping, MCA ligation
Permanent: MCA coagulation, MCA ligation
Give 3 advantages of the surgical MCAo model
Suitable for large animal models, high proportion of successful procedures, very reproducible, no hypothermia, low mortality, long-term observation possible
Give 3 disadvantages of the surgical MCAo model
Side effects of craniotomy (e.g. CSF leakage, surgical trauma), usually permanent occlusion so does not model recanalisation, surgical skill required
Name 3 methods of modelling embolic stroke
Microspheres, macrospheres, emboli, thrombin injection
What are the advantages of emboli and thrombin over microspheres and macrospheres?
Lysable with rtTPA
Give 3 advantages of the embolic MCAo model
Models the most common cause of human stroke, allows analysis of thrombolysis, no craniectomy unless using thrombin injection, no hypothermia, lower mortality than filament MCAo
Give 3 disadvantages of the embolic MCAo model
Low rate of successful MCAo, little control over site of clot lodgement, hard to determine effectiveness of reperfusion due to lack of certainty over occlusion
Describe photothrombosis
The use of 530nm laser light to induce the formation of a thrombus in a predefined anatomical region
Give 3 advantages of the photothrombosis MCAo model
Precise location of infarction, targeting functionally defined regions, high level of reproducibility, dura not opened, minimal mortality
Give 3 disadvantages of the photothrombosis MCAo model
Additional direct effects on brain function, endothelial lesion, expensive material, only useful for very specific study aims
Describe 3 differences between rodent and human brain vasculature
Rodents have increased capillary density, decreased inter-capillary diffusion distance, and increased CSF turnover
Give 3 advantages of larger animal models over rodents
Closer to human brain anatomy and function, imaging techniques easier, better monitoring of physiology
Give 3 disadvantages of larger animal models compared to rodents
Intensive in cost and labour, large variability, high mortality, animal welfare limitations, public and ethical concerns
What is the grey to white matter ratio in humans?
40:60
What is the grey to white matter ratio in a mouse?
90:10
What is the grey to white matter ratio in a rat?
85:15
What is the grey to white matter ratio in a chimpanzee?
60:40
Give 3 reasons why animals may create a roadblock in transition to human clinical trials?
1) Most models use young, healthy animals as using older animals is more expensive
2) No clinically relevant time point of treatment
3) Physiological parameters not controlled
Give 3 reasons why humans may pose a roadblock in transition from animal to human clinical trials?
1) Adequate drug concentrations not reached
2) Inappropriate time window used
3) Inclusion of patients not adjusted for the mode of drug action
4) Insufficient statistical power to prove efficacy
Give the 2 main haemorrhagic stroke models
Intra-striatal collagenase injection in rodents, and the blood infection model
Describe the intra-straital collagenase injection model
Bacterial collagenase injected into rodents destroys the basal lamina of cerebral blood vessels in a dose-dependent manner
Describe the blood infection model of haemorrhagic stroke
The direct injection of blood into the striatum
Describe what animal studies have revealed about immune system modulation in stroke
There is a biphasic response - activation followed by suppression. On day one, there is massive activation of peripheral immune cells with increased IL-6, interferon gamma, and MCP-1. By day four, immune suppression is occuring, with splenic and thymic atrophy, lower expression of pro-inflammatory cytokines, and increased apoptosis of stimulated cells
What is the major determinant of immune depression after stroke?
Infarct size
Why is immune system depression an issue in stroke?
30% of all stroke patients develop infections - 10% pneumonia, and 10% UTI. Pneumonia is the leading cause of death in stroke patients
Give 2 hallmarks of post-stroke immunodepression
Lymphocytopaenia and reduced monocyte responsiveness
How does neuroinflammation affect outcome from stroke?
It leads to secondary brain damage, with inflammatory cascades leading to infarct enlargement, and over-expression of adhesion molecules and chemokines leading to invasion by the systemic immune system
