Traumatic brain injury is one of the most complex CNS disorder

1. Animal Models in Traumatic
Brain Injury
Dr Amit Agrawal, MCh

2. TBI: Introduction
• Traumatic brain injury is one of the most complex
CNS disorder
• Survivors are at risk to develop
• Acute neurological deficits
• Persistent pathological changes
• Chronic neuropsychiatric
• Physical and cognitive disability

3. TBI: Introduction
• Consists of four overlapping phases
• Primary injury
• Evolution of the primary injury
• Secondary or additional injury
• Regeneration

4. TBI: Animal Models
• Animal models that mimic a single type of
primary impact resulting in TBI can help in
identifying signatures that are characteristic
or unique for the given type of TBI
• Animal models that reliably demonstrate
clinically relevant endpoints will expedite
development of new treatments,
diagnostics, preventive measures, and
rehabilitative strategies

5. TBI: Purpose of Animal Models
• To replicate certain pathological components
or phases of clinical trauma in experimental
animals
• To address pathology and/or treatment
• To understand the complex molecular
detrimental cascades initiated by trauma

6. TBI: Experimental Model Criteria
 The mechanical force used to induce injury is
controlled, reproducible, and quantifiable
 The inflicted injury is reproducible, quantifiable, and
mimics components of human conditions
 The injury outcome, measured by morphological,
physiological, biochemical, or behavioral parameters,
is related to the mechanical force causing the injury
 The intensity of the mechanical force used to inflict
injury should predict the outcome severity

7. TBI: Commonly Used Models
• Focal “impact loading”:
• Weight drop model (Fenney, Shohami)
• Fluid Percussion Injury model (Hayes, McIntosh)
• Controlled Cortical Impact model (Dixon, Hayes)
• Missile and ballistic Injury models (Carey, Williams. Tortella)
• Penetrating TBI model (Davidsson, Risling)
• Diffuse “Inertial loading”
• Impact
• Inertial acceleration model (Ono)
• Diffuse injury model (Cernak, Vink)
• Impact acceleration model (Marmarou)
• Non-impact
• Inertial acceleration models (Thibault, Genneralli, Meaney, Graham)
• Rotational TBI model (Davidsson, Risling)
• Blast TBI models

8. Challenges: The Pathophysiological
Heterogeneity
• The location
• Nature and severity of the primary injury
• Preexisting factors and conditions
• Age
• Health
• Gender
• Medication
• Alcohol and drug use
• Genetics

9. Animal Models: Challenges
• A reliable and reproducible animal model that reproduces
development/age- and gender-dependent responses to
traumatic brain injury
• Each is intended to mimic certain components of clinical TBI
• It is difficult to establish consistent models that include
most or all of the factors that contribute to post-traumatic
tissue damage
• Failure to utilize the most effective experimental design
• Unfortunately, results from animal models have had limited
diagnostic and therapeutic implications in the clinical setting

10. Limitations
• Incomplete understanding of the complexity
and diversity of secondary injury mechanisms
• Inability of the drugs to adequately cross the
blood-brain barrier
• Failure to assess clinically relevant behavioral
outcomes
• Pharmacogenetic/epigenetic variability

11. Conclusions
• There are numerous rodent models of TBI available
• Widely varying in their ability to model
pathomechanisms associated with human TBI
• Provide the experimental backbone for investigating
TBI pathomechanisms and for the initial testing of
neuro-protective compounds
• Considering the heterogeneity of human TBI,
scientific hypothesis should be tested in multiple
rodent models resulting in distinct types of injury

12. Future
• Cell culture models
• Cell culture is currently the most promising
alternative to animal research

13. References
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Neurosci. 2013 Feb;14(2):128-42.
• Marklund N, Hillered L. Animal modelling of traumatic brain injury in preclinical drug
development: where do we go from here? Br J Pharmacol. 2011 Oct;164(4):1207-29.
• Briones TL. Chapter 3 animal models of traumatic brain injury: is there an optimal model
that parallels human brain injury? Annu Rev Nurs Res. 2015;33(1):31-73.
• Rubovitch V, Ten-Bosch M, Zohar O, Harrison CR, Tempel-Brami C, Stein E, Hoffer BJ,
Balaban CD, Schreiber S, Chiu WT, Pick CG. A mouse model of blast-induced mild
traumatic brain injury. Exp Neurol. 2011 Dec;232(2):280-9.
• Loane DJ, Faden AI. Neuroprotection for traumatic brain injury: translational challenges
and emerging therapeutic strategies. Trends Pharmacol Sci. 2010 Dec;31(12):596-604.
• Janowitz T, Menon DK. Exploring new routes for neuroprotective drug development in
traumatic brain injury. Sci Transl Med. 2010 Apr 14;2(27):27rv1.
• Kabadi SV, Faden AI. Neuroprotective strategies for traumatic brain injury: improving
clinical translation. Int J Mol Sci. 2014 Jan 17;15(1):1216-36.
• Xiong Y, Zhang Y, Mahmood A, Chopp M. Investigational agents for treatment of
traumatic brain injury. Expert Opin Investig Drugs. 2015 Jun;24(6):743-60.
• Yarnell AM, Shaughness MC, Barry ES, Ahlers ST, McCarron RM, Grunberg NE. Blast
traumatic brain injury in the rat using a blast overpressure model. Curr Protoc Neurosci.
2013;Chapter 9:Unit 9.41.