The role of autophagy in spinal cord injury

Kanno, Haruo; Ozawa, Hiroshi; Sekiguchi, Akira; Itoi, Eiji

doi:10.4161/auto.5.3.7724

Cited by 82 publications

(51 citation statements)

References 37 publications

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“…This upregulation of G-CSF promotes autophagy in SCI Y Guo et al LC3B may maximize and prolong autophagy activity in neurons after treatment with G-CSF. Interestingly, we also find that most nuclei of LC3B-positive cells that are TUNEL positive are round and not shrunken or fragmented, suggesting that in at least some of these injured neurons autophagy may have an important protective role by inhibiting apoptosis at this early stage of SCI, a conclusion supported by Kanno et al 7 The role of autophagy activation during SCI remains a matter of debate. Many investigators regard autophagy as exerting a cytoprotective function that involves a mechanism for recycling injured cells and reducing damage against cell death.…”

Section: Discussionsupporting

confidence: 71%

“…4,5 In addition to apoptosis, recent findings have revealed that autophagy represents another mechanism involved with regulating programmed cell death after SCI. 6,7 Autophagy has an important role in the degradation of cytoplasmic constituents via the autophagosomal-lysosomal pathway. 8,9 This pathway provides a means through which damaged organelles, toxic agents and long-lived, unwanted proteins are degraded and recycled, thereby maintaining cellular homeostasis.…”

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confidence: 99%

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G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice

Guo

Liu

Zhang

et al. 2015

Laboratory Investigation

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Granulocyte colony-stimulating factor (G-CSF) was investigated for its capacity to induce autophagy and related neuroprotective mechanisms in an acute spinal cord injury model. To accomplish this goal, we established a mouse spinal cord hemisection model to test the effects of recombinant human G-CSF. The results showed that autophagy was activated after spinal cord injury and G-CSF appears to induce a more rapid activation of autophagy within injured spinal cords as compared with that of non-treated animals. Apoptosis as induced in mechanically injured neurons with G-CSF treatment was enhanced after inhibiting autophagy by 3-methyladenine (3-MA), which partially blocked the neuroprotective effect of autophagy as induced by G-CSF. In addition, G-CSF inhibited the activity of the NF-κB signal pathway in neurons after mechanical injury. We conclude that G-CSF promotes autophagy by inhibiting the NF-κB signal pathway and protects neuronal structure after spinal cord injury. We therefore suggest that G-CSF, which rapidly induces autophagy after spinal cord injury to inhibit neuronal apoptosis, may thus provide an effective auxiliary therapeutic intervention for spinal cord injury.

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Section: Discussionsupporting

confidence: 71%

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confidence: 99%

G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice

Guo

Liu

Zhang

et al. 2015

Laboratory Investigation

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“…However, pyknosis may be observed as a result of various cell death pathways (Burgoyne 1999). This realization prompted us to explore alternative processes for delayed death since we have recently observed that cells die even several hours after washout of kainate (Mazzone et al 2010) even if, in the field of spinal cord injury research, a common view is that the early cell death is predominantly by necrosis followed by apoptosis (Liu et al 1997;Baptiste and Fehlings 2006) that can be caspase-dependent (Liu et al 2002;Yu et al 2009) and caspase-independent (Eliasson et al 1997;Mandir et al 2000;Verdaguer et al 2002;Won et al 2002;Yuan et al 2003;Cho and Toledo-Pereyra 2008;Kanno et al 2009). Recently, an alternative cell death pathway, termed parthanatos, involving hyperactivity of poly(ADPribose) polymerase-1 (PARP-1) has been considered important to spinal cord injury (Scott et al 1999;Genovese et al 2005;Wu et al 2009) because it would strongly impair the mitochondrial energy stores.…”

Section: Introductionmentioning

confidence: 97%

Kainate-Mediated Excitotoxicity Induces Neuronal Death in the Rat Spinal Cord In Vitro via a PARP-1 Dependent Cell Death Pathway (Parthanatos)

2010

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Kainate is an effective excitotoxic agent to lesion spinal cord networks, thus providing an interesting model for investigating basic mechanisms of spinal cord injury. The present study aimed at revealing the type and timecourse of cell death in rat neonatal spinal cord preparations in vitro exposed to 1 h excitotoxic insult with kainate. Substantial numbers of neurons rather than glia showed pyknosis (albeit without necrosis and with minimal apoptosis occurrence) already apparent on kainate washout and peaking 12 h later with dissimilar spinal topography. Neurons appeared to suffer chiefly through a process involving anucleolytic pyknosis mediated by strong activation of poly(ADP-ribose)polymerase-1 (PARP-1) that generated poly ADP-ribose and led to nuclear translocation of the apoptotic inducing factor (AIF) with DNA damage. This process had the hallmarks of parthanatos-type neuronal death. The PARP-1 inhibitor 6-5(H)-phenathridione applied immediately after kainate washout significantly prevented pyknosis in a dose-dependent fashion and inhibited PARP-1-dependent nuclear AIF translocation. Conversely, the caspase-3 inhibitor II was ineffective against neuronal damage. Our results suggest that excitotoxicity of spinal networks was mainly directed to neurons and mediated by PARP-1 death pathways, indicating this mechanism as a potential target for neuroprotection to limit the acute damage to the local circuitry.

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“…26,27 Activation of autophagy started at 4 hours post-SCI, peaked at 3 days, and lasted for 21 days. The LC3-positive cells were located in neurons, astrocytes, and oligodendrocytes.…”

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Acute spinal cord injury in rats should target activated autophagy

Hou

Zhang

Tang

2014

SPI

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Object Autophagy is a cellular mechanism of maintaining balance between protein synthesis and degradation; the latter can be induced by starvation and neurodegenerative disease. Spinal cord injury (SCI) induces necrosis and apoptosis. Autophagic flux has not yet been defined, especially the potential role of autophagy in relation to apoptosis in different tissue cells. The object of this study was to investigate the occurrence of autophagic flux and the potential role of autophagy and apoptosis post-SCI in rats. Methods Following creation of SCI in rats, activation of autophagic flux was detected at the protein (LC3, beclin1, and p62) and mRNA (beclin1) levels and on electron microscopy images. Distribution of LC3, colocalization of activated caspase-3, and changes in expression levels of bcl-2 and Bax were assessed to investigate the potential role of autophagy and apoptosis. Sprague-Dawley rats were used, and T9–10 hemitransection was performed. Expression levels of LC3, beclin1, p62, bcl-2, and Bax were assessed by Western blot analysis, and beclin1 mRNA levels were assessed by reverse transcription–polymerase chain reaction. Distribution of LC3 and colocalization of activated caspase-3 were analyzed by immunohistochemistry. Autophagosome formation was investigated by electron microscopy. Results The authors found a dramatic elevation in LC3 and beclin1 levels near the scar region. Using double staining, they observed that upregulation of LC3 started at 4 hours in neurons and at 3 days in astrocytes after SCI. Confocal images indicated that the percentage of neurons with apoptosis was reduced, while the percentage of astrocytes with apoptosis was high at 4 hours, 8 hours, and 1 day post-SCI but decreased sharply at 3 days. Electron microscopy images provided evidence of autophagosome formation. Elimination of p62 indicated occurrence of autophagic flux. Expression levels of bcl-2 and Bax were increased and decreased, respectively, near the injury site. Conclusions The results of this research demonstrated that autophagic flux is activated after SCI. Potentially, inhibition of apoptosis could be a target to promote neural recovery.

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The role of autophagy in spinal cord injury

Cited by 82 publications

References 37 publications

G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice

G-CSF promotes autophagy and reduces neural tissue damage after spinal cord injury in mice

Kainate-Mediated Excitotoxicity Induces Neuronal Death in the Rat Spinal Cord In Vitro via a PARP-1 Dependent Cell Death Pathway (Parthanatos)

Acute spinal cord injury in rats should target activated autophagy

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