Diffuse axonal injury in brain trauma: insights from alterations in neurofilaments

Abstract

Traumatic brain injury (TBI) from penetrating or closed forces to the cranium can result in a range of forms of neural damage, which culminate in mortality or impart mild to significant neurological disability. In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes. The neurofilament triplet proteins are key structural cytoskeletal elements, which may also be important contributors to the tensile strength of axons. This has significant implications with respect to how axons may respond to TBI. It is not known, however, whether neurofilament compaction and the cytoskeletal changes that evolve following axonal injury represent a component of a protective mechanism following damage, or whether they serve to augment degeneration and progression to secondary axotomy. Here we review the structure and role of neurofilament proteins in normal neuronal function. We also discuss the processes that characterize DAI and the resultant alterations in neurofilaments, highlighting potential clues to a possible protective or degenerative influence of specific neurofilament alterations within injured neurons. The potential utility of neurofilament assays as biomarkers for axonal injury is also discussed. Insights into the complex alterations in neurofilaments will contribute to future efforts in developing therapeutic strategies to prevent, ameliorate or reverse neuronal degeneration in the central nervous system (CNS) following traumatic injury.

Keywords: NFL; biomarkers; diffuse axonal injury; diffuse brain trauma; neurofilament; neurofilament compaction; traumatic axonal injury; traumatic brain injury.

Figure 1

Intracellular injury cascade in DAI. (A) In response to trauma, the axolemma either undergoes primary mechanical failure, exposing the cytosol to the extracellular space, or mechanosensitive sodium channels are activated, resulting in a flux of sodium into the axoplasm. (B) Perturbation to the ionic equilibrium results in directional change in flow of calcium, resulting in intracellular accumulation. (C) Calcium can be sequestered in the mitochondria, however this generates reactive oxygen species that may disrupt oxidative metabolism and have downstream consequences with respect to oxidative damage to an axon in crisis. Similarly, elevated calcium can activate calcium-dependent calpains (a), caspases (b) and phosphatases (c) all of which mediate cytoskeletal breakdown. (D) Cytoskeletal breakdown results in impaired axonal transport, axonal swelling and neurofilament compaction.