Animal Models of Stroke

Question 1

Name the three main uses of animal models

Answer 1

Studying pathophysiology, validating clinical observations, and drug development

Question 2

Name 3 models of focal cerebral ischaemia

Answer 2

Proximal middle cerebral artery occlusion, distal middle cerebral artery occlusion, thromboembolic middle cerebral artery occlusion, endothelin model, photothrombosis model

Question 3

Name 2 animal models of global cerebral ischaemia

Answer 3

Four vessel occlusion, two vessel occlusion, cardiac arrest and resuscitation

Question 4

Describe the filament middle cerebral artery occlusion model (filament MCAo)

Answer 4

A filament is inserted to occlude the coronal carotid artery and the origin of the middle cerebral artery temporarily - typically for 45-90 minutes

Question 5

Give 3 advantages of the filament MCAo model

Answer 5

Relatively easy operation, no craniectomy required, can assess reperfusion

Question 6

Give 3 disadvantages of the filament MCAo model

Answer 6

Hypothermia, weight loss, high mortality, short observation period, high degree of variability

Question 7

Name 2 surgical models of transient MCA occlusion, and 2 models of permanent occlusion

Answer 7

Transient: MCA clipping, MCA ligation
Permanent: MCA coagulation, MCA ligation

Question 8

Give 3 advantages of the surgical MCAo model

Answer 8

Suitable for large animal models, high proportion of successful procedures, very reproducible, no hypothermia, low mortality, long-term observation possible

Question 9

Give 3 disadvantages of the surgical MCAo model

Answer 9

Side effects of craniotomy (e.g. CSF leakage, surgical trauma), usually permanent occlusion so does not model recanalisation, surgical skill required

Question 10

Name 3 methods of modelling embolic stroke

Answer 10

Microspheres, macrospheres, emboli, thrombin injection

Question 11

What are the advantages of emboli and thrombin over microspheres and macrospheres?

Answer 11

Lysable with rtTPA

Question 12

Give 3 advantages of the embolic MCAo model

Answer 12

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

Question 13

Give 3 disadvantages of the embolic MCAo model

Answer 13

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

Question 14

Describe photothrombosis

Answer 14

The use of 530nm laser light to induce the formation of a thrombus in a predefined anatomical region

Question 15

Give 3 advantages of the photothrombosis MCAo model

Answer 15

Precise location of infarction, targeting functionally defined regions, high level of reproducibility, dura not opened, minimal mortality

Question 16

Give 3 disadvantages of the photothrombosis MCAo model

Answer 16

Additional direct effects on brain function, endothelial lesion, expensive material, only useful for very specific study aims

Question 17

Describe 3 differences between rodent and human brain vasculature

Answer 17

Rodents have increased capillary density, decreased inter-capillary diffusion distance, and increased CSF turnover

Question 18

Give 3 advantages of larger animal models over rodents

Answer 18

Closer to human brain anatomy and function, imaging techniques easier, better monitoring of physiology

Question 19

Give 3 disadvantages of larger animal models compared to rodents

Answer 19

Intensive in cost and labour, large variability, high mortality, animal welfare limitations, public and ethical concerns

Question 20

What is the grey to white matter ratio in humans?

Answer 20

40:60

Question 21

What is the grey to white matter ratio in a mouse?

Answer 21

90:10

Question 22

What is the grey to white matter ratio in a rat?

Answer 22

85:15

Question 23

What is the grey to white matter ratio in a chimpanzee?

Answer 23

60:40

Question 24

Give 3 reasons why animals may create a roadblock in transition to human clinical trials?

Answer 24

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

Question 25

Give 3 reasons why humans may pose a roadblock in transition from animal to human clinical trials?

Answer 25

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

Question 26

Give the 2 main haemorrhagic stroke models

Answer 26

Intra-striatal collagenase injection in rodents, and the blood infection model

Question 27

Describe the intra-straital collagenase injection model

Answer 27

Bacterial collagenase injected into rodents destroys the basal lamina of cerebral blood vessels in a dose-dependent manner

Question 28

Describe the blood infection model of haemorrhagic stroke

Answer 28

The direct injection of blood into the striatum

Question 29

Describe what animal studies have revealed about immune system modulation in stroke

Answer 29

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

Question 30

What is the major determinant of immune depression after stroke?

Answer 30

Infarct size

Question 31

Why is immune system depression an issue in stroke?

Answer 31

30% of all stroke patients develop infections - 10% pneumonia, and 10% UTI. Pneumonia is the leading cause of death in stroke patients

Question 32

Give 2 hallmarks of post-stroke immunodepression

Answer 32

Lymphocytopaenia and reduced monocyte responsiveness

Question 33

How does neuroinflammation affect outcome from stroke?

Answer 33

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