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

Siedler DG, Chuah MI, Kirkcaldie MT, Vickers JC, King AE - Front Cell Neurosci (2014)

Bottom Line: In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes.This has significant implications with respect to how axons may respond to TBI.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.

View Article: PubMed Central - PubMed

Affiliation: Wicking Dementia Research and Education Centre, Medical Sciences Precinct Hobart, TAS, Australia ; School of Medicine, University of Tasmania Hobart, TAS, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

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.
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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.

Mentions: The exact mechanisms that initiate secondary degeneration in DAI are yet to be completely characterized, although in vivo and in vitro experimental models provide some insight. For example, fluid percussion models of injury in mice have reinforced the notion that mechanical stretching and disruption of the axolemma are a primary event, with axonal damage detectable at 2 h (He et al., 2004) and 4 h post-injury (Spain et al., 2010). In vitro, such damage precedes ionic imbalance (Smith et al., 1999), which may precipitate axonal swellings, secondary axotomy and Wallerian degeneration (Johnson et al., 2013). Axonal alterations may be driven by increases in intra-axonal calcium levels. In DAI, mechanical disruption creating breaches in the axolemma has been suggested as a mechanism of extracellular calcium entry (Farkas et al., 2006; Kilinc et al., 2009). However, activation of transmembrane calcium channels that mediate the extracellular influx may also be essential. Stimulation of mechanosensitive sodium channels by axonal deformation may reverse sodium/calcium transporters and activate voltage-gated calcium channels, culminating in the influx of extracellular calcium (Figure 1; Wolf et al., 2001). Other calcium channels that have been implicated include voltage-gated L-type and T-type calcium channels (Knoferle et al., 2010). However, there is also evidence for intracellular calcium release in axonal injury (Staal et al., 2010; Stirling et al., 2014). A study of long-term primary neuron cultures subjected to an axonal stretch injury observed a biphasic calcium elevation, and indicated that both intracellular and extracellular calcium contribute to the overall increase in axoplasmic calcium (Staal et al., 2010). The link between the release of extracellular and intracellular calcium stores will be an important focus of future research, with a recent study showing that expression of stromal interaction molecules may perpetuate elevated cytosolic calcium, as its suppression has been shown to improve survival after an axonal cut injury (Hou et al., 2014).


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

Siedler DG, Chuah MI, Kirkcaldie MT, Vickers JC, King AE - Front Cell Neurosci (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4269130&req=5

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.
Mentions: The exact mechanisms that initiate secondary degeneration in DAI are yet to be completely characterized, although in vivo and in vitro experimental models provide some insight. For example, fluid percussion models of injury in mice have reinforced the notion that mechanical stretching and disruption of the axolemma are a primary event, with axonal damage detectable at 2 h (He et al., 2004) and 4 h post-injury (Spain et al., 2010). In vitro, such damage precedes ionic imbalance (Smith et al., 1999), which may precipitate axonal swellings, secondary axotomy and Wallerian degeneration (Johnson et al., 2013). Axonal alterations may be driven by increases in intra-axonal calcium levels. In DAI, mechanical disruption creating breaches in the axolemma has been suggested as a mechanism of extracellular calcium entry (Farkas et al., 2006; Kilinc et al., 2009). However, activation of transmembrane calcium channels that mediate the extracellular influx may also be essential. Stimulation of mechanosensitive sodium channels by axonal deformation may reverse sodium/calcium transporters and activate voltage-gated calcium channels, culminating in the influx of extracellular calcium (Figure 1; Wolf et al., 2001). Other calcium channels that have been implicated include voltage-gated L-type and T-type calcium channels (Knoferle et al., 2010). However, there is also evidence for intracellular calcium release in axonal injury (Staal et al., 2010; Stirling et al., 2014). A study of long-term primary neuron cultures subjected to an axonal stretch injury observed a biphasic calcium elevation, and indicated that both intracellular and extracellular calcium contribute to the overall increase in axoplasmic calcium (Staal et al., 2010). The link between the release of extracellular and intracellular calcium stores will be an important focus of future research, with a recent study showing that expression of stromal interaction molecules may perpetuate elevated cytosolic calcium, as its suppression has been shown to improve survival after an axonal cut injury (Hou et al., 2014).

Bottom Line: In this regard, diffuse axonal injury (DAI) is a major neuronal pathophenotype of TBI and is associated with a complex set of cytoskeletal changes.This has significant implications with respect to how axons may respond to TBI.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.

View Article: PubMed Central - PubMed

Affiliation: Wicking Dementia Research and Education Centre, Medical Sciences Precinct Hobart, TAS, Australia ; School of Medicine, University of Tasmania Hobart, TAS, Australia.

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.

No MeSH data available.


Related in: MedlinePlus