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Animal models of traumatic brain injury

Key Points

  • Traumatic brain injury (TBI) is a leading cause of mortality and morbidity both in civilian life and on the battlefield worldwide.

  • Animal models are essential for studying the biomechanical, cellular and molecular aspects of human TBI that cannot be addressed in the clinical setting, as well as for developing and characterizing novel therapeutic interventions.

  • Nevertheless, promising neuroprotective drugs, which were identified as being effective in animal TBI models, have all failed in Phase II or Phase III clinical trials.

  • This Review provides a broad overview of current knowledge of animal models of TBI, identifies the issues and challenges of therapeutic strategies in preclinical studies and highlights research strategies for improving animal models and therapeutic efficacy.

  • To achieve a therapeutic breakthrough in TBI, multifaceted approaches are probably required, including the development of new clinically relevant models, refinements of established models and functional tests, consideration of systemic insults and multimodality monitoring, identification of specific and sensitive biomarkers, and optimization of therapeutic dosing and timing of single and combination treatments, as well as improvement in clinical trial design and operation.

  • In addition, more research into the effects of age, sex and species or strain on the outcome of TBI is necessary. Additional studies in improving brain drug delivery systems and monitoring of target drug levels and drug effects are warranted in both animal models and the clinical setting.

Abstract

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity both in civilian life and on the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs that were identified as being effective in animal TBI models have all failed in Phase II or Phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies.

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Figure 1: Experimental set-ups for the animal models of TBI.

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Acknowledgements

We thank the three anonymous referees for their excellent comments, and we apologize to those researchers whose work has not been cited owing to space limitations. This work was supported by the National Institutes of Health grants RO1 NS062002 (Y.X.), PO1 NS042345 (A.M. and M.C.) and PO1 NS023393 (M.C.).

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Glossary

Diffuse axonal injury

(DAI). DAI is characterized by impaired axoplasmic flow that progresses to axotomy and is typically identified by the presence of the amyloid-β precursor protein, as revealed by immunohistochemical staining.

Modified NSS

The modified NSS (neurological severity score) is a composite of motor, sensory, reflex and balance tests for use in rats.

Neurological severity score

(NSS). The NSS is a reliable tool for evaluating neurological damage in closed head trauma in mice and rats, and assesses both motor function and behaviour.

Phosphorylated tauopathy

This is the accumulation of hyperphosphorylated tau protein (a highly soluble microtubule-associated protein), which causes the formation of neurofibrillary tangles. These tangles are a pathological hallmark of tauopathies, which are a group of diseases including Alzheimer's disease, frontal temporal dementia with Parkinsonism and corticobasal degeneration.

Biomarkers

A biomarker is a specific biochemical, molecular, anatomical or physiological characteristic that is used to measure or indicate the presence or progress of disease or the effects of treatment.

Glasgow coma scale

(GCS). The GCS is a standardized scale that is used to measure the level of consciousness, to assess the degree of brain impairment and to identify the seriousness of injury in relation to outcome after TBI. The score is determined by summing the ratings of how the patient responds to certain standard stimuli by opening their eyes, giving a verbal response and giving a motor response. A high score of 13 to 15 indicates a mild brain injury, a score of 9 to 12 reflects a moderate brain injury and a score of 3 to 8 reflects a severe brain injury.

Glasgow outcome scale

(GOS). The GOS is an outcome score in which individuals with TBI are assigned to one of five categories: dead, vegetative state, severe disability, moderate disability or good recovery. The extended GOS (GOSe) provides more detailed categorization into eight categories by subdividing the categories of severe disability, moderate disability and good recovery into lower and upper categories.

Erythropoietin

(EPO). EPO is a glycoprotein hormone secreted by the kidney in adult mammals and by the liver in the fetus; it acts on stem cells of the bone marrow to stimulate red blood cell production (that is, erythropoiesis).

Tissue plasminogen activator

(tPA). tPA is an enzyme that catalyses the conversion of plasminogen to plasmin and is used to dissolve blood clots rapidly and selectively, especially in the treatment of heart attacks and ischaemic stroke.

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Xiong, Y., Mahmood, A. & Chopp, M. Animal models of traumatic brain injury. Nat Rev Neurosci 14, 128–142 (2013). https://doi.org/10.1038/nrn3407

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