Animal models of traumatic brain injury Flashcards Preview

NMH: Module 2 > Animal models of traumatic brain injury > Flashcards

Flashcards in Animal models of traumatic brain injury Deck (23)
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1

Primitive level: steps of TBI?

mechanical input -> primary injury -> secondary injuries ->
secondary injuries and restorative processes influence ong term outcome

2

Describe impact effects of primary injury?

- tissue deformation
- contusions
- lacerations
- haemorrhages

3

Describe non-impact effects of primary injury?

- diffuse axonal injury (DAI)
- swelling

4

Examples of focal injury?

- contusions
- lacerations
- haemorrhages

5

Examples of diffuse injury?

- DAI
- swelling/herniation
- ischaemia
- vascular injury

6

Describe the mechanisms behind secondary injury in TBI

Primary injury -> Ca2+ influx -> NT release -> excitotoxicity
-> mitochondrial damage -> ROS -> gene exp -> BBB opening -> inflammation -> oedema -> raised ICP -> herniation

Inflammation -> release of DAMPs, chemokines, cytokines -> neutrophils, monocytes -> microglia/astrocytes

7

Why are in vivo models of TBI necessary?

Single models can't truly reproduce the complex pathophysiological spectrym of TBI

(need to ID mechanisms and test therapies)

8

How to assess the validity of a model?

- face validity: same phenomenology

- construct validity: similar underlying mechanisms

- aetiological validity: similar changes in aetiology

- predictive validity: predictive value, accuracy and reliability

9

List similarities between mammalian TBI models and real TBI

- gross histopathology (contusion, BBB disruption, cell loss, brain atrophy)
- molecular changes (inflammation/apoptosis/oxidative stress/axonal injury)
- functional deficits (memory and learning deficits)
- long term effects (detectable in rodents up to 1 yr)

10

Differences between primary mammalian TBI models and real TBI

Anaesthesia (not in human TBI): type of anaesthesia used can affect functional and histological outcome e.g. diff. cell count

Craniotomy (not in human TBI): surgery is a brain injury itself; MRI shows craniotomy results in oedema/inflammation

11

Primary problems of in vivo TBI models

- Drug selection: drugs rushed to trials (e.g. CRASH study gave steroids for TBI for anti-inflamm but this increased mortality)

- Trial design: low participant number, single vs multi-centre trials

- Patient selection: mild/mod/severe TBI, confounding factors, sex?

- Endpoints: GCS, motor/cognitive impairments, survival

12

Describe and evaluate in vitro TBI models

Use
- immortalised cell lines
- primary cell cultures
- organtypic slices
- acute explants
- 3D organoids

Induce TBI through:
- stretch
- shearing
- weight drop
- blast injury
- stir, transection, acceleration

PROS
- repeatable
- controlled biomechanics
- environmental and pathophysiological isolation
- high throught + screening approaches

CONS
- snapshot
- clinical improvement?
- functional outcome?
- network effects?
- extra-CNS effects?

13

List examples of in vivo TBI models

- drosophilia (invertebrates)
- zebrafish (non-mammalian)

MAMMALIAN:
- controlled cortical impact
- fluid percussion
- weight drop
- penetrating ballistic model
- blast injury
- rotational model
- Maryland model

14

Describe and evaluate drosophilia (invertebrate) model method

- inside container w/ loaded spring to fling them -> TBI
- pipette pressure pulse to hit head

Causes vacuoles and cell loss

PROS
- cheap
- no ethical restrictions
- fast life cycle
- easy genetic modification

CONS
- reproducibility
- no skull
- different biomechanics
- morphological differences

15

Describe and evaluate zebrafish (non-mammalian) model method

- stab wound injury
- weight drop
- focussed ultrasound

Causes inflammation, cell loss, delta (behaviour)

PROS
- fast life cycle
- less ethical restrictions
- study behaviour
- vertebrate


CONS
- reproducibility
- different biomechanics
- different metabolism

16

Describe and evaluate controlled cortical impact TBI method

Impactor accelerated to hit brain without affecting the skull -> focal contusion

Damage depends on speed and depth of injury

PROS
- highly reproducilbe
- biomechanical control
- species scalability
- low mortality
- age-effects

CONS
- craniotomy required (affecting results)
- contusion not always a feature of clinical TBI
- anaesthesia could affect outcome

17

Describe and evaluate fluid percussion as a TBI model

Fluid pressure wave hits brain -> mixed focal contusion and diffuse injury

Damage depends on amount of pressure

PROS
- highly reproducible
- biomechanical control
- species scalability
- age-effects

CONS
- craniotomy required (could affect results)
- high mortality

18

Describe and evaluate weight drop models for TBI

Free falling guided weight hits either exposed dura/exposed skull/steel disc/skull

PROS
- closed head model
- easy operation

CONS
- reproducibility
- craniotomy required
- high mortality

19

Describe and evaluate penetrating ballistic model in TBI

Air-rifle pellets/probes mimic penetrating brain injury (shockwave or temporary cavity)

PROS
- similar biomechanics to clinical penetrating TBI
- species scalability

CONS
- reproducibility
- bone fragments in skull
- rare clinically

20

Describe and evaluate blast injury model for TBI

Shock tube/open field explosions mimic blast wave, rotational effects + heat/gas/smoke

PROS
- similar biomechanics
- species scalability

CONS
- reproducibility
- rare clinically

21

Describe rotational model for TBI

Dart shot to rotate head to create whiplash

22

Describe Maryland model for TBI

Steel balls hit metal component on head

Models frontal injury and coup-countre coup

23

Illustrate the process of preclinical to clinical translation using TBI models as
example

E.g. progesterone

Pre-clinical TBI studies: progesterone had beneficial effects

Phase II: beneficial effects

Multi-centre study: adverse effects

WHY?
- different application route (intraperitoneal pre-clin VS oral/iv clinical)
- suboptimal endpoints
- few dose-response studies in animals