Protective effects of erythropoietin in experimental spinal cord injury by reducing the C/EBP-homologous protein expression

Hong, Zhenghua; Hong, Huaxing; Chen, Haixiao; Wang, Zhangfu; Hong, Dun

doi:10.1179/1743132811y.0000000026

Cited by 18 publications

(13 citation statements)

References 24 publications

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“…Recent studies indicate that ER stress is an early tissue reaction after SCI in different models, including mechanical trauma and hypoxia. 8, 10, 11, 12, 13, 27 Here we show a fast activation of a range of UPR responses after SCI, including the expression of the proximal components ATF4 and XBP1, major transcription factors governing this pathway, in addition to the upregulation of downstream target genes. Remarkably, UPR activation was also observed in regions distant from the primary injury zone, suggesting the activation of a broad ER stress response in the spinal cord after damage.…”

Section: Discussionmentioning

confidence: 65%

Activation of the unfolded protein response enhances motor recovery after spinal cord injury

Valenzuela

Collyer

Armentano³

et al. 2012

Cell Death Dis

134

127

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Spinal cord injury (SCI) is a major cause of paralysis, and involves multiple cellular and tissular responses including demyelination, inflammation, cell death and axonal degeneration. Recent evidence suggests that perturbation on the homeostasis of the endoplasmic reticulum (ER) is observed in different SCI models; however, the functional contribution of this pathway to this pathology is not known. Here we demonstrate that SCI triggers a fast ER stress reaction (1–3 h) involving the upregulation of key components of the unfolded protein response (UPR), a process that propagates through the spinal cord. Ablation of X-box-binding protein 1 (XBP1) or activating transcription factor 4 (ATF4) expression, two major UPR transcription factors, leads to a reduced locomotor recovery after experimental SCI. The effects of UPR inactivation were associated with a significant increase in the number of damaged axons and reduced amount of oligodendrocytes surrounding the injury zone. In addition, altered microglial activation and pro-inflammatory cytokine expression were observed in ATF4 deficient mice after SCI. Local expression of active XBP1 into the spinal cord using adeno-associated viruses enhanced locomotor recovery after SCI, and was associated with an increased number of oligodendrocytes. Altogether, our results demonstrate a functional role of the UPR in SCI, offering novel therapeutic targets to treat this invalidating condition.

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Section: Discussionmentioning

confidence: 65%

Activation of the unfolded protein response enhances motor recovery after spinal cord injury

Valenzuela

Collyer

Armentano³

et al. 2012

Cell Death Dis

134

127

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“…24 In addition, modulation of ER stress molecules BiP, CHOP, XBP-1, and ATF4 decreased motoneuron death 17 and improved functional recovery after SCI. [25][26][27][28] Our own work with axotomized RGCs has shown that manipulating CHOP and XBP-1 in opposite directions, by deleting CHOP or by overexpressing XBP-1s, exerts striking RGC-protective effects. 16 Because XBP-1 regulates numerous genes that are involved in multiple cellular functions, it is important to define the downstream mechanism by which XBP-1 contributes to neuroprotection.…”

Section: Therapeutic Strategies Targeting Er Stress For Neuroprotectionmentioning

confidence: 99%

“…ER stress markers also have been detected in cortex after stroke 21, 22 and in motoneurons in a mouse model of ALS 23 . Moreover, modulation of ER stress protected cortical neurons in models of ischemia and TBI 24 , decreased spinal motoneuron death 17, 23 and improved functional recovery after SCI 25-28 . ER stress has been reviewed extensively in relation to chronic neurodegenerative diseases 29-33 .…”

Section: Introductionmentioning

confidence: 99%

“…23 Moreover, modulation of ER stress protected cortical neurons in models of ischemia and TBI, 24 decreased spinal motoneuron death, 17,23 and improved functional recovery after SCI. [25][26][27][28] ER stress has been reviewed extensively in relation to chronic neurodegenerative diseases. [29][30][31][32][33] It has, for example, been suggested to be a critical mechanism for neurodegeneration in several hereditary motor neuron diseases, in which ER stress is precipitated by accumulation of the mutant ER-resident protein seipin within moroneurons.…”

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confidence: 99%

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Neuronal endoplasmic reticulum stress in axon injury and neurodegeneration

Liu

Selzer

et al. 2013

Annals of Neurology

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Injuries to CNS axons result not only in Wallerian degeneration of the axon distal to the injury, but also in death or atrophy of the axotomized neurons, depending on injury location and neuron type. No method of permanently avoiding these changes has been found, despite extensive knowledge concerning mechanisms of secondary neuronal injury. The autonomous endoplasmic reticulum (ER) stress pathway in neurons has recently been implicated in retrograde neuronal degeneration. In addition to the emerging role of ER morphology in axon maintenance, we propose that ER stress is a common neuronal response to disturbances in axon integrity and a general mechanism for neurodegeneration. Thus manipulation of the ER stress pathway could have important therapeutic implications for neuroprotection.

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“…Recent studies indicate that ER stress is an early tissue reaction after SCI in different models, including mechanical trauma and hypoxia. 8,[10][11][12][13]27 Here we show a fast activation of a range of UPR responses after SCI, including the expression of the proximal components ATF4 and XBP1, major transcription factors governing this pathway, in addition to the upregulation of downstream target genes. Remarkably, UPR activation was also observed in regions distant from the primary injury zone, suggesting the activation of a broad ER stress response in the spinal cord after damage.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Unfolded Protein Response Enhances Motor Recovery after Spinal Cord Injury

et al. 2013

View full text Add to dashboard Cite

Spinal cord injury (SCI) is a major cause of paralysis, and involves multiple cellular and tissular responses including demyelination, inflammation, cell death and axonal degeneration. Recent evidence suggests that perturbation on the homeostasis of the endoplasmic reticulum (ER) is observed in different SCI models; however, the functional contribution of this pathway to this pathology is not known. Here we demonstrate that SCI triggers a fast ER stress reaction (1-3 h) involving the upregulation of key components of the unfolded protein response (UPR), a process that propagates through the spinal cord. Ablation of X-box-binding protein 1 (XBP1) or activating transcription factor 4 (ATF4) expression, two major UPR transcription factors, leads to a reduced locomotor recovery after experimental SCI. The effects of UPR inactivation were associated with a significant increase in the number of damaged axons and reduced amount of oligodendrocytes surrounding the injury zone. In addition, altered microglial activation and pro-inflammatory cytokine expression were observed in ATF4 deficient mice after SCI. Local expression of active XBP1 into the spinal cord using adeno-associated viruses enhanced locomotor recovery after SCI, and was associated with an increased number of oligodendrocytes. Altogether, our results demonstrate a functional role of the UPR in SCI, offering novel therapeutic targets to treat this invalidating condition.

show abstract

Protective effects of erythropoietin in experimental spinal cord injury by reducing the C/EBP-homologous protein expression

Abstract: Endoplasmic reticulum (ER) stress was triggered at the early stage of SCI. Increased expression of CHOP can be found in the injured segment of the spinal cord after injury. EPO treatment could prevent pathological alterations from severe spinal cord injury by reducing expression of CHOP.

Cited by 18 publications

References 24 publications

Activation of the unfolded protein response enhances motor recovery after spinal cord injury

Activation of the unfolded protein response enhances motor recovery after spinal cord injury

Neuronal endoplasmic reticulum stress in axon injury and neurodegeneration

Activation of the Unfolded Protein Response Enhances Motor Recovery after Spinal Cord Injury

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