Glycogen accumulation in axons after stretch injury

Maxwell, William L.; Irvine, A; Strang, R.; Graham, David I.; Adams, J. Hume; Gennarelli, Thomas A.

doi:10.1007/bf01217301

Cited by 17 publications

(9 citation statements)

References 26 publications

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“…The current study's use of YFP-expressing mice provides an unprecedented view into the pathogenesis of traumatic induced axonal injury, allowing for the precise identification of the initiation of axonal injury and the subsequent progression of axonal swelling and disconnection, as well as the ongoing proximal and distal axonal response. To date, others have studied traumatic axonal injury using optic nerve stretch Maxwell et al, 1990;Saatman FIG. 9.…”

Section: Discussionmentioning

confidence: 99%

Traumatic Axonal Injury in the Optic Nerve: Evidence for Axonal Swelling, Disconnection, Dieback, and Reorganization

Wang

Hamm

Povlishock

2011

Journal of Neurotrauma

112

146

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Traumatic axonal injury (TAI) is a major feature of traumatic brain injury (TBI) and is associated with much of its morbidity. To date, significant insight has been gained into the initiating pathogenesis of TAI. However, the nature of TAI within the injured brain precludes the consistent evaluation of its specific anterograde and retrograde sequelae. To overcome this limitation, we used the relatively organized optic nerve in a central fluid percussion injury (cFPI) model. To improve the visualization of TAI, we utilized mice expressing yellow fluorescent protein (YFP) in their visual pathways. Through this approach, we consistently generated TAI in the optic nerve and qualitatively and quantitatively evaluated its progression over a 48-h period in YFP axons via confocal microscopy and electron microscopy. In this model, delayed axonal swelling with subsequent disconnection were the norm, together with the fact that once disconnected, both the proximal and distal axonal segments revealed significant dieback, with the proximal swellings showing regression and reorganization, while the distal swellings persisted, although showing signs of impending degeneration. When antibodies targeting the C-terminus of amyloid precursor protein (APP), a routine marker of TAI were employed, they mapped exclusively to the proximal axonal segments without distal targeting, regardless of the survival time. Concomitant with this evolving axonal pathology, focal YFP fluorescence quenching occurred and mapped precisely to immunoreactive loci positive for Texas-Red-conjugated-IgG, indicating that blood-brain barrier disruption and its attendant edema contributed to this phenomenon. This was confirmed through the use of antibodies targeting endogenous YFP, which demonstrated the retention of intact immunoreactive axons despite YFP fluorescence quenching. Collectively, the results of this study within the injured optic nerve provide unprecedented insight into the evolving pathobiology associated with TAI.

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Section: Discussionmentioning

confidence: 99%

Traumatic Axonal Injury in the Optic Nerve: Evidence for Axonal Swelling, Disconnection, Dieback, and Reorganization

Wang

Hamm

Povlishock

2011

Journal of Neurotrauma

112

146

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“…Most of the glycogen in the brain resides in astrocytes [6,19]. It is of interest that in many of the pathological conditions where astrocyte swelling occurs, there is also an increase in glycogen content, including traumatic brain injury [5,19,39,44], ischemia and stroke [16,24], radiation injury [30,38,41], experimental hepatic encephalopathy [43], chronic hepatocerebral degeneration [23], experimental allergic encephalomyelitis [14], and Creutzfeldt±Jacob disease [26,32,42]. These in vivo reports again serve to illustrate the association between astroglial swelling and glycogen content, although the precise timing of these events is not known.…”

Section: Discussionmentioning

confidence: 99%

Association between cell swelling and glycogen content in cultured astrocytes

Dombro

Bender

Norenberg

2000

Intl J of Devlp Neuroscience

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Treatment of cultured rat astrocytes with hypotonic media or with 1 mM glutamate for 90 min caused cell swelling and a significant increase in glycogen content. Conversely, treatment with hypertonic media caused cell shrinkage with a corresponding decrease in astrocyte glycogen, which was proportional to the increasing osmolality of the hypertonic media. The glutamate receptor antagonist, MK-801, lowered both the glutamate-induced swelling and glycogen increase. These findings demonstrate a correlation between changes in cell volume and astrocyte glycogen content. This may explain the increased astrocytic glycogen observed in many neuropathological conditions where astrocyte swelling occurs. Because glycogen represents the largest energy reserve in the central nervous system, a swelling-induced disturbance in glycogen metabolism may lead to abnormal glial-neuronal interactions resulting in impaired brain bioenergetics.

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“…39,78,79 Owing, in part, to the isolated nature of the white matter injury, these models have proven very useful in evaluating ultrastructural changes in axons after trauma as well as identifying pathological chemical cascades that may represent important therapeutic targets. 34,39,47,[78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93] These models, however, are not widely used or practical for high-throughput therapy evaluation. Nonetheless, they represent a potential stepwise bridge between in vitro and in vivo therapy development.…”

Section: Lissencephalic Animal Models Of Taimentioning

confidence: 99%

Therapy Development for Diffuse Axonal Injury

Smith

Hicks

Povlishock

2013

Journal of Neurotrauma

174

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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Glycogen accumulation in axons after stretch injury

Cited by 17 publications

References 26 publications

Traumatic Axonal Injury in the Optic Nerve: Evidence for Axonal Swelling, Disconnection, Dieback, and Reorganization

Traumatic Axonal Injury in the Optic Nerve: Evidence for Axonal Swelling, Disconnection, Dieback, and Reorganization

Association between cell swelling and glycogen content in cultured astrocytes

Therapy Development for Diffuse Axonal Injury

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