Review
Experimental models of traumatic axonal injury

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Abstract

Traumatic brain injury (TBI) is one of the leading causes of death in people under 45 years of age worldwide. Such injury is characterized by a wide spectrum of mechanisms of injury and pathologies. Traumatic axonal injury (TAI), originally described as diffuse axonal injury, is one of the most common pathological features of TBI and is thought to be responsible for the long-lasting neurological impairments following TBI. Since the late 1980s a series of in vivo and in vitro experimental models of TAI have been developed to better understand the complex mechanisms of axonal injury and to define the relationship between mechanical forces and the structural and functional changes of injured axons. These models are designed to mimic as closely as possible the clinical condition of human TAI and have greatly improved our understanding of different aspects of TAI. The present review summarizes the most widely used experimental models of TAI. Focusing in particular on in vivo models, this survey aims to provide a broad overview of current knowledge and controversies in the development and use of the experimental models of TAI.

Introduction

Traumatic brain injury (TBI), a devastating and common problem in today’s society, is one of the most frequent causes of morbidity and mortality in both industrialized and developing countries.1 Diffuse axonal injury (DAI), a common and important pathological feature of TBI, was first described by Strich in 1956 and named by Adams in 1982.[2], [3] The term is applied to the widespread destruction of white matter tracts by TBI, which makes a major contribution to neurological dysfunction in TBI patients.4 Although coined as “diffuse”, the pattern of axonal injury in the white matter is more accurately described as “multifocal”, and the term “traumatic axonal injury” (TAI) has been suggested as being more appropriate for this type of TBI.[5], [6] Recently, the descriptor TAI has been applied to experimental studies that have attempted to elucidate the mechanisms of axonal injury after TBI.

TAI in patients with head injury is usually associated with poor outcome and often results in burdensome health-care costs, and a more complete understanding of TAI is required in order to develop more effective treatments. In response to this need, a growing number of animal models have been introduced and characterized since the late 1980s. Technological breakthroughs, including new methodologies in radiological examination, improved neurochemical and molecular technologies, and transgenic animals, now allow researchers to pursue in-depth studies of TAI. The available animal models, however, are not without drawbacks. In particular, the complexity of the in vivo condition may result in a limited accessibility to the tissue of interest and prevent real-time and spatial measurements of biological or mechanical parameters.7 Several in vitro experimental approaches have been developed to complement the utility of in vivo models. Focusing principally on animal models, the following sections address the different models of TAI with a view to guiding and improving future research endeavors in this field.

Section snippets

Experimental models of traumatic axonal injury

The experimental models of TAI generally include in vivo models, in vitro models, physical models, and mathematical models (Table 1).[6], [7], [8], [9] Because physical and mathematical models are principally intended for biomechanical analysis of TAI, their purpose is distinct from that of in vivo and in vitro models; these are therefore not discussed in the present review. Multiple approaches and markers have been used in these diverse models to detect and characterize TAI. These commonly

The requirements of ideal experimental model

Diverse experimental models have been employed extensively to investigate the causes of TAI, to replicate the sequence of events taking place in patients, and to test the efficacy of new therapies. To maximize the reliability and validity of data obtained in these different models, experimental models should meet the following criteria:

  • (i)

    TAI is the predominant pathological change taking place post-injury; other types of injury not associated with TAI are avoided.

  • (ii)

    The injury mechanism resembles, as

Conclusions

Since the late 1980s many investigators have attempted to develop models that can accurately replicate different aspects of TAI. Data from studies using in vivo models, complemented by in vitro, physical, and mathematical models, have contributed to our growing understanding of TAI. In vivo models cast light on injury-loading conditions and permit the exploration of pathological, physiological, and behavioral changes taking place in TBI. They also permit the evaluation of new therapeutic and

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