Characterization of a distinct set of intra-axonal ultrastructural changes associated with traumatically induced alteration in axolemmal permeability

Pettus, Edward H.; Povlishock, John T.

doi:10.1016/0006-8993(96)00113-8

Cited by 231 publications

(133 citation statements)

References 33 publications

Supporting

Mentioning

124

Contrasting

Unclassified

Order By: Relevance

“…On the other hand, axons that undergo dynamic deformation but do not swell may nonetheless suffer subtle yet important pathophysiological changes, including an increase in intra-axonal calcium and sodium concentrations or mitochondrial dysfunction, as suggested by previous in vivo and in vitro studies Pettus and Povlishock, 1996;Pettus et al, 1994;Smith et al, 1999b;Staal et al, 2010;Wolf et al, 2001;Yuen et al, 2009). These processes are thought to contribute to physiological dysfunction of white matter pathways, such as the reduction in conduction velocity that has been observed in mTBI (Baker et al, 2002;Kumar et al, 2009;Nuwer et al, 2005).…”

Section: Discussionmentioning

confidence: 97%

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Browne

Chen²,

Meaney³

et al. 2011

Journal of Neurotrauma

216

172

View full text Add to dashboard Cite

Until recently, mild traumatic brain injury (mTBI) or ''concussion'' was generally ignored as a major health issue. However, emerging evidence suggests that this injury is by no means mild, considering it induces persisting neurocognitive dysfunction in many individuals. Although little is known about the pathophysiological aspects of mTBI, there is growing opinion that diffuse axonal injury (DAI) may play a key role. To explore this possibility, we adapted a model of head rotational acceleration in swine to produce mTBI by scaling the mechanical loading conditions based on available biomechanical data on concussion thresholds in humans. Using these input parameters, head rotational acceleration was induced in either the axial plane (transverse to the brainstem; n = 3), causing a 10-to 35-min loss of consciousness, or coronal plane (circumferential to the brainstem; n = 2), which did not produce a sustained loss of consciousness. Seven days following injury, immunohistochemical analyses of the brains revealed that both planes of head rotation induced extensive axonal pathology throughout the white matter, characterized as swollen axonal bulbs or varicosities that were immunoreactive for accumulating neurofilament protein. However, the distribution of the axonal pathology was different between planes of head rotation. In particular, more swollen axonal profiles were observed in the brainstems of animals injured in the axial plane, suggesting an anatomic substrate for prolonged loss of consciousness in mTBI. Overall, these data support DAI as an important pathological feature of mTBI, and demonstrate that surprisingly overt axonal pathology may be present, even in cases without a sustained loss of consciousness.

show abstract

Section: Discussionmentioning

confidence: 97%

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Browne

Chen²,

Meaney³

et al. 2011

Journal of Neurotrauma

216

172

View full text Add to dashboard Cite

show abstract

“…31,61 A similar focal loss of microtubules in injured axons has also been found after optic nerve stretch injury in the guinea pig as well as rat TBI models. 47,87,158,159 With the complete loss of microtubules, axonal transport is totally derailed, triggering unmitigated accumulation of the cargoes. In turn, the resulting swelling can lead to disconnection and degeneration.…”

Section: Cytoskeleton Stabilizationmentioning

confidence: 99%

“…2D). 158,[161][162][163][164] While there is debate of the mechanisms, poration may by a primary mechanical effect or a secondary event triggered by a chemical dissolution of the axolemma. 58,165 In either case, therapies that address membrane fluidity and repair, such as polyethylene glycol and the surfactant, Poloxamer 188, may be beneficial for axons with modest or transient openings of the axolemma or for those that are at risk of a breach of the axolemma.…”

Section: Ion Homeostasismentioning

confidence: 99%

“…2D and E and 3F). 158 While evidence to support the mechanisms involved in this mitochondrial damage is incomplete, most data point to the likelihood that the same intra-axonal calcium loads that activate the cysteine proteases also contribute to mitochondrial calcium overloading, which in the face of other factors, including the activation of oxygen radicals, trigger mitochondrial permeability transition. This leads to the demise of the mitochondria and their ability to provide the high energy phosphates needed to maintain local axonal structure and function.…”

Section: Mitochondria Protectionmentioning

confidence: 99%

See 1 more Smart Citation

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

Self Cite

174

146

View full text Add to dashboard Cite

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.

show abstract

“…Others have also reported axonal pathology after experimental TBI and clarified the pathophysiology of the injury process [26,39,41,42,43]. Following FP injury, there is an acute swelling of axons and marked intra-axonal ultrastructural changes [14,41,43].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms and Treatment of Progressive Damage After Traumatic Brain Injury

Bramlett¹

2003

View full text Add to dashboard Cite

Characterization of a distinct set of intra-axonal ultrastructural changes associated with traumatically induced alteration in axolemmal permeability

Cited by 231 publications

References 33 publications

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Mild Traumatic Brain Injury and Diffuse Axonal Injury in Swine

Therapy Development for Diffuse Axonal Injury

Mechanisms and Treatment of Progressive Damage After Traumatic Brain Injury

Contact Info

Product

Resources

About