Local down-regulation of myelin-associated glycoprotein permits axonal sprouting with chronic nerve compression injury

Gupta, Ranjan; Rummler, Laura S.; Palispis, Winnie A.; Truong, Linh; Chao, Tom; Rowshan, Kasra; Mozaffar, Tahseen; Steward, Oswald

doi:10.1016/j.expneurol.2006.02.134

Cited by 56 publications

(52 citation statements)

References 33 publications

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“…Notably, the chronic nerve compression model does not induce mechanical allodynia or thermal hyperalgesia, instead resulting in progressive decreases in mechanical sensitivity (52). In our study, the lack of detectable NaV1.8 hnRNA in the SNE-injured nerve (Fig.…”

Section: Discussionmentioning

confidence: 68%

Relationship of Axonal Voltage-gated Sodium Channel 1.8 (NaV1.8) mRNA Accumulation to Sciatic Nerve Injury-induced Painful Neuropathy in Rats

Ruangsri

Lin²,

Mulpuri

et al. 2011

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 68%

Relationship of Axonal Voltage-gated Sodium Channel 1.8 (NaV1.8) mRNA Accumulation to Sciatic Nerve Injury-induced Painful Neuropathy in Rats

Ruangsri

Lin²,

Mulpuri

et al. 2011

Journal of Biological Chemistry

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“…Following CNC injury, Schwann cells in the compressed region downregulate MAG as part of the program of demyelination. 13 Analysis of electron micrographs at the same time point reveal an increase in the number of small unmyelinated fibers grouped together by nonmyelinating Schwann cells into structures known as Remak bundles, which is consistent with axonal sprouting (Fig. 3).…”

Section: Downregulation Of Myelin-associated Proteins and Axonal Spromentioning

confidence: 68%

“…3). 13 In children, MAG has been demonstrated to enhance axonal growth. 17 In adults, however, MAG is to known to inhibit axonal regeneration and neurite outgrowth via p75-mediated activation of Rho and binding to the Nogo receptor.…”

Section: Downregulation Of Myelin-associated Proteins and Axonal Spromentioning

confidence: 99%

“…Interestingly, intraneural injections of MAG at the time of injury prevents CNC-induced sprouting, providing further evidence that downregulation of MAG is permissive of axonal sprouting. 13 As with demyelination and Schwann cell apoptosis/proliferation, axonal sprouting occurs at time when there is no evidence of axonal injury.…”

Section: Downregulation Of Myelin-associated Proteins and Axonal Spromentioning

confidence: 99%

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Understanding the mechanisms of entrapment neuropathies

Gupta

2009

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Compression neuropathies are highly prevalent, debilitating conditions with variable functional recovery following surgical decompression. Due to the limited amount of human nerve tissue available for analysis, a number of animal models have been created to help investigators understand the molecular and cellular pathogenesis of chronic nerve compression (CNC) injury. Evidence suggests that CNC injury induces concurrent Schwann cell proliferation and apoptosis in the early stages of the disorder. These proliferating Schwann cells downregulate myelin proteins, leading to local demyelination and remyelination in the region of injury. In addition, the downregulation of myelin proteins, in particular myelin-associated glycoprotein, allows for axonal sprouting. Interestingly, these changes occur in the absence of both morphological and electrophysiological evidence of axonal damage. This is in direct contrast to acute injuries, such as transection or crush, which are characterized by axonal injury followed by Wallerian degeneration. Because the accepted trigger for Schwann cell dedifferentiation is axonal injury, an alternate mechanism for Schwann response must exist in CNC injury. In vitro studies of pure Schwann cells have shown that these cells can respond directly to mechanical stimuli by downregulating myelin proteins and proliferating. These studies suggest that although the reciprocal relationship between neurons and glial cells is maintained, chronic nerve compression injury is a Schwann cell-mediated disease.

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“…24,46 Mechanical loading of SCs alters the expression of genes that permit axonal sprouting, a response observed in later stages of chronic compression injury. 6,47 Our results reported here, colocalizing SCs with the messenger protein Src activated in response to demyelinating biophysical stimuli, further implicate SCs as the prime mediator of CNC injury.…”

Section: Discussionmentioning

confidence: 72%

Biophysical stimulation induces demyelination via an integrin‐dependent mechanism

Lin

Frieboes

Forootan

et al. 2012

Annals of Neurology

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Objective: Chronic nerve compression (CNC) injuries occur when peripheral nerves are subjected to sustained mechanical forces, with increasing evidence implicating Schwann cells as key mediators. Integrins, a family of transmembrane adhesion molecules that are capable of intracellular signaling, have been implicated in a variety of biological processes such as myelination and nerve regeneration. In this study, we seek to define the physical stimuli mediating demyelination and to determine whether integrin plays a role in the demyelinating response. Methods: We used a previously described in vitro model of CNC injury where myelinating neuron-Schwann cell cocultures were subjected to independent manipulations of hydrostatic pressure, hypoxia, and glucose deprivation in a custom bioreactor. We assessed whether demyelination increased in response to applied manipulation and determined whether integrin-associated signaling cascades are upregulated. Results: Biophysical stimulation of neural tissue induced demyelination and Schwann cell proliferation without neuronal or glial cytotoxicity or apoptosis. Although glucose deprivation and hypoxia independently had minor effects on myelin stability, together they potentiated the demyelinating effects of hydrostatic compression, and in combination, significantly destabilized myelin. Biophysical stimuli transiently increased phosphorylation of the integrin-associated tyrosine kinase Src within Schwann cells. Silencing this integrin signaling cascade blocked Src activation and prevented pressure-induced demyelination. Colocalization analysis indicated that Src is localized within Schwann cells. Interpretation: These results indicate that myelin is sensitive to CNC injury and support the novel concept that myelinating cocultures respond directly to mechanical loading via activating an integrin signaling cascade.

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Local down-regulation of myelin-associated glycoprotein permits axonal sprouting with chronic nerve compression injury

Cited by 56 publications

References 33 publications

Relationship of Axonal Voltage-gated Sodium Channel 1.8 (NaV1.8) mRNA Accumulation to Sciatic Nerve Injury-induced Painful Neuropathy in Rats

Relationship of Axonal Voltage-gated Sodium Channel 1.8 (NaV1.8) mRNA Accumulation to Sciatic Nerve Injury-induced Painful Neuropathy in Rats

Understanding the mechanisms of entrapment neuropathies

Biophysical stimulation induces demyelination via an integrin‐dependent mechanism

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