A qualitative and quantitative analysis of the response of the retinal ganglion cell soma after stretch injury to the adult guinea-pig optic nerve

Maxwell, William L.; Islam, Md. Nazrul; Graham, David I.; Gennarelli, Thomas A.

doi:10.1007/bf01666527

Cited by 36 publications

(25 citation statements)

References 51 publications

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“…This, coupled with the observation of lengthening of the axotomized process at 48 hr and the overall reduction in axonal swelling size at the same time, argues that those neurons sustaining TAI are not dying but rather may be attempting a reparative response. Using a dissimilar optic nerve stretch injury model, Maxwell et al (1994) alluded to a similar possibility in a subpopulation of injured neurons, whereas another group (Emery et al, 2000) has recently identified TBI-induced expression of markers associated with neuronal regeneration in the same brain regions found herein to sustain perisomatic TAI.…”

Section: Discussionmentioning

confidence: 90%

Traumatically Induced Axotomy Adjacent to the Soma Does Not Result in Acute Neuronal Death

Singleton¹,

et al. 2002

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Traumatic axonal injury (TAI), a consequence of traumatic brain injury (TBI), results from progressive pathologic processes initiated at the time of injury. Studies attempting to characterize the pathology associated with TAI have not succeeded in following damaged and/or disconnected axonal segments back to their individual neuronal somata to determine their fate. To address this issue, 71 adult male Sprague Dawley rats were subjected to moderate central fluid percussion injury and killed between 30 min and 7 d after injury. Antibodies to the C terminus of ␤-amyloid precursor protein (APP) identified TAI in continuity with individual neuronal somata in the mediodorsal neocortex, the hilus of the dentate gyrus, and the dorsolateral thalamus. These somata were followed with immunocytochemical markers of neuronal injury targeting phosphorylated 200 kDa neurofilaments (RMO-24), altered protein translation (phosphorylated eukaryotic translation initiation factor 2␣), and cell death [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)], with parallel electron microscopic (EM) assessment. Despite the finding of TAI within 20-50 m of the soma, no evidence of cell death, long associated with proximal axotomy, was seen via TUNEL or routine light microscopy/electron microscopy. Rather, there was rapid onset (Ͻ6 hr after injury) subcellular change associated with impaired protein synthesis identified by EM, immunocytochemical, and Western blot analyses. When followed 7 d after injury, these abnormalities did not reveal dramatic progression. Rather, some somata showed evidence of potential reorganization and repair. This study demonstrates a novel somatic response to TAI in the perisomatic domain and also provides insight into the multifaceted pathology associated with TBI.

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Section: Discussionmentioning

confidence: 90%

Traumatically Induced Axotomy Adjacent to the Soma Does Not Result in Acute Neuronal Death

Singleton¹,

et al. 2002

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“…In contrast to crush or cut injury where axons and surrounding glial cells are acutely damaged, diffuse injury to the nervous system results in slow axonal disconnections with distinct morphological characteristics (Maxwell et al, 1994). Mechanical strain applied to mammalian axons has previously been shown to result in alterations in the properties of the axolemma, leading to Fig.…”

Section: Subsets Of Rgcs Increase Gap-43 and ␣-Tubulin Mrna Levels Afmentioning

confidence: 99%

Target contact regulates GAP-43 and ?-tubulin mRNA levels in regenerating retinal ganglion cells

et al. 1998

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Axotomy of vertebrate neurons leads to the transient upregulation of GAP-43 and alpha-tubulin. In adult zebrafish retina, mRNA levels of both genes were increased in retinal ganglion cells after optic nerve lesion following a similar time course. At 5 days after crush, the mRNA level of GAP-43 was increased nearly 20 times, whereas a 6-fold increase was observed for alpha-tubulin. Subsequently, upon target reinnervation, mRNA levels of both genes were downregulated and were 2-fold higher than normal at 25 days after crush. Stretching the optic nerve that results in diffuse axonal lesions led to the expression of both genes in identical subsets of retinal ganglion cells. When regeneration was prevented by removing a piece of the optic nerve, mRNA levels remained elevated. Disruption of axonal transport by colchicine and vinblastine led to the induction of both genes in normal retina. Blocking electrical activity with tetrodotoxin had no effect. This indicates that retrogradely transported signals induced by target contact regulate GAP-43 and alpha-tubulin transcription. Furthermore, the joint regulation of GAP-43 and alpha-tubulin mRNA levels after different kinds of lesion suggests that a common pathway underlies the regulation of neuronal GAP-43 and alpha-tubulin gene expression. In contrast, distinct mechanisms may control the extent and maintenance of increased mRNA levels of these genes.

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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

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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A qualitative and quantitative analysis of the response of the retinal ganglion cell soma after stretch injury to the adult guinea-pig optic nerve

Cited by 36 publications

References 51 publications

Traumatically Induced Axotomy Adjacent to the Soma Does Not Result in Acute Neuronal Death

Traumatically Induced Axotomy Adjacent to the Soma Does Not Result in Acute Neuronal Death

Target contact regulates GAP-43 and ?-tubulin mRNA levels in regenerating retinal ganglion cells

Therapy Development for Diffuse Axonal Injury

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