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

Animal models of traumatic brain injury Flashcards

1
Q

Primitive level: steps of TBI?

A

mechanical input -> primary injury -> secondary injuries ->

secondary injuries and restorative processes influence ong term outcome

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2
Q

Describe impact effects of primary injury?

A
  • tissue deformation
  • contusions
  • lacerations
  • haemorrhages
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3
Q

Describe non-impact effects of primary injury?

A
  • diffuse axonal injury (DAI)

- swelling

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4
Q

Examples of focal injury?

A
  • contusions
  • lacerations
  • haemorrhages
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5
Q

Examples of diffuse injury?

A
  • DAI
  • swelling/herniation
  • ischaemia
  • vascular injury
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6
Q

Describe the mechanisms behind secondary injury in TBI

A

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

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7
Q

Why are in vivo models of TBI necessary?

A

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

(need to ID mechanisms and test therapies)

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8
Q

How to assess the validity of a model?

A
  • face validity: same phenomenology
  • construct validity: similar underlying mechanisms
  • aetiological validity: similar changes in aetiology
  • predictive validity: predictive value, accuracy and reliability
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9
Q

List similarities between mammalian TBI models and real TBI

A
  • 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)
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10
Q

Differences between primary mammalian TBI models and real TBI

A

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

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11
Q

Primary problems of in vivo TBI models

A
  • 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
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12
Q

Describe and evaluate in vitro TBI models

A

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?
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13
Q

List examples of in vivo TBI models

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

MAMMALIAN:

  • controlled cortical impact
  • fluid percussion
  • weight drop
  • penetrating ballistic model
  • blast injury
  • rotational model
  • Maryland model
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14
Q

Describe and evaluate drosophilia (invertebrate) model method

A
  • 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
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15
Q

Describe and evaluate zebrafish (non-mammalian) model method

A
  • 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
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16
Q

Describe and evaluate controlled cortical impact TBI method

A

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
Q

Describe and evaluate fluid percussion as a TBI model

A

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
Q

Describe and evaluate weight drop models for TBI

A

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
Q

Describe and evaluate penetrating ballistic model in TBI

A

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
Q

Describe and evaluate blast injury model for TBI

A

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

PROS

  • similar biomechanics
  • species scalability

CONS

  • reproducibility
  • rare clinically
21
Q

Describe rotational model for TBI

A

Dart shot to rotate head to create whiplash

22
Q

Describe Maryland model for TBI

A

Steel balls hit metal component on head

Models frontal injury and coup-countre coup

23
Q

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

A

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

NMH: Module 2 (33 decks)

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