Traumatic Axonal Injury Induces Proteolytic Cleavage of the Voltage-Gated Sodium Channels Modulated by Tetrodotoxin and Protease Inhibitors

Iwata, Atsushi; Stys, Peter K.; Wolf, John A.; Chen, Xiaohan; Taylor, Andrew G.; Meaney, David F.; Smith, Douglas H.

doi:10.1523/jneurosci.0515-03.2004

Cited by 197 publications

(184 citation statements)

References 48 publications

(94 reference statements)

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“…These changes in ion flux could be responsible for the acute behavioral hypersensitivity produced in the absence of immediate axonal degeneration. Together with the results from this study, such findings suggest that immediate behavioral hypersensitivity in this model of transient compression may result from an immediate release of proinflammatory cytokines by resident cells, or via altered primary afferent electrical activity that occurs prior to the neuronal degeneration or macrophage infiltration observed later at day 7 (Figure 3 & Figure 5) (Waxman et al, 1999;Boucher et al, 2000;Cuellar et al, 2004;Sommer and Kress, 2004;Iwata et al, 2004;Xie et al, 2006;Kirita et al, 2007). Further studies are required to determine the role of these inflammatory mediators as a function of nerve root compression mechanics.…”

Section: Discussionsupporting

confidence: 61%

“…Neurons in the DRG become hyperexcitable immediately after injury to their axons, which can also lead to extended periods of spontaneous ectopic neuronal firing and pain (Sheen and Chung, 1993;Waxman et al, 1999;Boucher et al, 2000;Iwata et al, 2004;Zhang et al, 2004;Kirita et al, 2007). Several studies suggest that ectopic firing after axonal damage results from calcium influx or altered sodium channel subtype expression (Waxman et al, 1999;Boucher et al, 2000;Iwata et al, 2004;Kirita et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies suggest that ectopic firing after axonal damage results from calcium influx or altered sodium channel subtype expression (Waxman et al, 1999;Boucher et al, 2000;Iwata et al, 2004;Kirita et al, 2007). These changes in ion flux could be responsible for the acute behavioral hypersensitivity produced in the absence of immediate axonal degeneration.…”

Section: Discussionmentioning

confidence: 99%

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Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity

Hubbard¹,

Winkelstein²

2008

Experimental Neurology

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Increased sensitivity to mechanical stimuli produced by transient cervical nerve root compression is dependent on the severity of applied load. In addition, trauma in the nervous system induces local inflammation, Wallerian degeneration, and a host of other degenerative processes leading to axonal dysfunction. Here, axonal degeneration and inflammation were assessed following transient dorsal root compression to establish a relationship between conditions for dorsal root axonal changes and those previously established for the onset and maintenance of mechanical behavioral hypersensitivity (26.3mN and 38.2mN, respectively). Compression loads were applied over a range (0-110mN) known to produce sustained behavioral hypersensitivity. CD68-and NF200-immunoreactivity, as well as axonal pathological changes, were assessed in the dorsal root to investigate the load thresholds requisite for inducing macrophage infiltration and axonal degeneration relative to those thresholds for producing the onset and persistence of behavioral hypersensitivity. Neurofilament accumulation and the depletion of NF200-immunoreactivity in the region of compressed tissue were produced for loads that produce mechanical behavioral hypersensitivity. A 50 th -percentile load threshold was determined (31.6mN) governing the onset of NF200 depletion. However, CD68-immunoreactivity was increased for nearly all loads, suggesting that macrophage recruitment may not be directly related to nerve root-mediated behavioral hypersensitivity. This study provides new evidence for thresholdmediated degenerative changes in the context of behavioral hypersensitivity following nerve root compression.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity

Hubbard¹,

Winkelstein²

2008

Experimental Neurology

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“…Two general models have emerged that induce uniaxial (one direction) stretching of axons spanning two populations of neurons via either rapid extension of an elastic substrate in the longitudinal direction of the attached axons or using a pressurized fluid jet. 31,33,58,61,62,[95][96][97][98] Important findings from these models include demonstration of primary rupture of axonal microtubules, evolving proteolysis, and loss of ionic homeostasis, collectively revealing multiple potential therapeutic targets as discussed below.…”

Section: In-vitro Models Of Taimentioning

confidence: 99%

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

171

146

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Diffuse axonal injury (DAI) remains a prominent feature of human traumatic brain injury (TBI) and a major player in its subsequent morbidity. The importance of this widespread axonal damage has been confirmed by multiple approaches including routine postmortem neuropathology as well as advanced imaging, which is now capable of detecting the signatures of traumatically induced axonal injury across a spectrum of traumatically brain-injured persons. Despite the increased interest in DAI and its overall implications for brain-injured patients, many questions remain about this component of TBI and its potential therapeutic targeting. To address these deficiencies and to identify future directions needed to fill critical gaps in our understanding of this component of TBI, the National Institute of Neurological Disorders and Stroke hosted a workshop in May 2011. This workshop sought to determine what is known regarding the pathogenesis of DAI in animal models of injury as well as in the human clinical setting. The workshop also addressed new tools to aid in the identification of this axonal injury while also identifying more rational therapeutic targets linked to DAI for continued preclinical investigation and, ultimately, clinical translation. This report encapsulates the oral and written components of this workshop addressing key features regarding the pathobiology of DAI, the biomechanics implicated in its initiating pathology, and those experimental animal modeling considerations that bear relevance to the biomechanical features of human TBI. Parallel considerations of alternate forms of DAI detection including, but not limited to, advanced neuroimaging, electrophysiological, biomarker, and neurobehavioral evaluations are included, together with recommendations for how these technologies can be better used and integrated for a more comprehensive appreciation of the pathobiology of DAI and its overall structural and functional implications. Lastly, the document closes with a thorough review of the targets linked to the pathogenesis of DAI, while also presenting a detailed report of those target-based therapies that have been used, to date, with a consideration of their overall implications for future preclinical discovery and subsequent translation to the clinic. Although all participants realize that various research gaps remained in our understanding and treatment of this complex component of TBI, this workshop refines these issues providing, for the first time, a comprehensive appreciation of what has been done and what critical needs remain unfulfilled.

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“…Injured neurons also experience decreased cellular ATP from ischemia, as well as mitochondrial damage due to calcium accumulation (Ahmed et al, 2000;Schinder et al, 1996;Verweij et al, 2000;Young, 1992), leading to compromised sodium-potassium ATPase activity with resultant cell depolarization (Tavalin et al, 1995(Tavalin et al, , 1997. Coupled with stretchinduced delayed depolarization, changes in membrane potential promote the opening of tetrodotoxin-sensitive sodium channels (Iwata et al, 2004;Wolf et al, 2001b), reversal of sodium-calcium exchangers (Wolf et al, 2001b), and activation of voltage-sensitive calcium channels (Vacher et al, 2008). These findings highlight the complexity of posttraumatic accumulation of [Ca 2þ ] i detected following in vitro mechanical cell injury.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effects of Selective N-Type VGCC Blockade on Stretch-Injury-Induced Calcium Dynamics in Cortical Neurons

Shahlaie

Lyeth

Gurkoff

et al. 2010

Journal of Neurotrauma

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Acute elevation in intracellular calcium ([Ca 2þ ] i ) following traumatic brain injury (TBI) can trigger cellular mechanisms leading to neuronal dysfunction and death. The mechanisms underlying these processes are not completely understood, but calcium influx through N-type voltage-gated calcium channels (VGCCs) appears to play a central role. The present study examined the time course of [Ca 2þ ] i flux, glutamate release, and loss of cell viability following injury using an in vitro neuronal-glial cortical cell-culture model of TBI. The effects of N-channel blockade with SNX-185 (e.g. o-conotoxin TVIA) before or after injury were also examined. Neuronal injury produced a transient elevation in [Ca 2þ ] i , increased glutamate release, and resulted in neuronal and glial death. SNX-185 administered before or immediately after cell injury reduced glutamate release and increased the survival of neurons and astrocytes, whereas delayed treatment did not improve cell survival but significantly facilitated the return of [Ca 2þ ] i to baseline levels. The new findings that N-type VGCCs are critically involved in injury-induced glutamate release and recovery of [Ca 2þ ] i argue for continued investigation of this treatment strategy for the clinical management of TBI. In particular, SNX-185 may represent an effective class of drugs that can significantly protect injured neurons from the secondary insults that commonly occur after TBI.

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Traumatic Axonal Injury Induces Proteolytic Cleavage of the Voltage-Gated Sodium Channels Modulated by Tetrodotoxin and Protease Inhibitors

Cited by 197 publications

References 48 publications

Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity

Dorsal root compression produces myelinated axonal degeneration near the biomechanical thresholds for mechanical behavioral hypersensitivity

Therapy Development for Diffuse Axonal Injury

Neuroprotective Effects of Selective N-Type VGCC Blockade on Stretch-Injury-Induced Calcium Dynamics in Cortical Neurons

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