Phosphatidylethanolamine-Binding Protein 1 Ameliorates Ischemia-Induced Inflammation and Neuronal Damage in the Rabbit Spinal Cord

In a previous study, we utilized a proteomic approach and found a significant reduction in phosphatidylethanolamine-binding protein 1 (PEBP1) protein level in the spinal cord at 3 h after ischemia. In the present study, we investigated the role of PEBP1 against oxidative stress in NSC34 cells in vitro, and ischemic damage in the rabbit spinal cord in vivo. We generated a PEP-1-PEBP1 fusion protein to facilitate the penetration of blood-brain barrier and intracellular delivery of PEBP1 protein. Treatment with PEP-1-PEBP1 significantly decreased cell death and the induction of oxidative stress in NSC34 cells. Furthermore, administering PEP-1-PEBP1 did not show any significant side effects immediately before and after ischemia/reperfusion. Administration of PEP-PEBP1 improved the Tarlov’s neurological score at 24 and 72 h after ischemia, and significantly improved neuronal survival at 72 h after ischemia based on neuronal nuclei (NeuN) immunohistochemistry, Flouro-Jade B staining, and western blot study for cleaved caspase 3. PEP-1-PEBP1 administration decreased oxidative stress based on malondialdehyde level, advanced oxidation protein products, and 8-iso-prostaglandin F2α in the spinal cord. In addition, inflammation based on myeloperoxidase level, tumor necrosis factor-α level, and high mobility group box 1 level was decreased by PEP-1-PEBP1 treatment at 72 h after ischemia. Thus, PEP-1-PEBP1 treatment, which decreases oxidative stress, inflammatory cytokines, and neuronal death, may be an effective therapeutic strategy for spinal cord ischemia.

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MLN4924 Exerts a Neuroprotective Effect against Oxidative Stress via Sirt1 in Spinal Cord Ischemia-Reperfusion Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7283639 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

Sifei Yu ◽

Lei Xie ◽

Zhuochao Liu ◽

Changwei Li ◽

Yu Liang

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Ischemia Reperfusion Injury ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Sirtuin 1

Oxidative stress is a leading contributor to spinal cord ischemia-reperfusion (SCIR) injury. Recently, MLN4924, a potent and selective inhibitor of the NEDD8-activating enzyme, was shown to exert a neuroprotective effect against oxidative stress in vitro. However, it is unknown whether MLN4924 plays a protective role against SCIR injury. In the present study, we found that MLN4924 treatment significantly attenuated oxidative stress and neuronal cell death induced by H2O2 in SH-SY-5Y neural cells and during rat SCIR injury. Furthermore, MLN4924 administration restored neurological and motor functions in rats with SCIR injury. Mechanistically, we found that MLN4924 protects against H2O2- and SCIR injury-induced neurodegeneration by regulating sirtuin 1 (Sirt1) expression. Collectively, these findings demonstrate the neuroprotective role of MLN4924 against oxidative stress in SCIR injury via Sirt1.

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Hydrogen Sulfide Inhibits Autophagic Neuronal Cell Death by Reducing Oxidative Stress in Spinal Cord Ischemia Reperfusion Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/8640284 ◽

2017 ◽

Vol 2017 ◽

pp. 1-15 ◽

Cited By ~ 20

Author(s):

Lei Xie ◽

Sifei Yu ◽

Kai Yang ◽

Changwei Li ◽

Yu Liang

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Cell Death ◽

Hydrogen Sulfide ◽

Motor Function ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Autophagic Cell Death

Autophagy is upregulated in spinal cord ischemia reperfusion (SCIR) injury; however, its expression mechanism is largely unknown; moreover, whether autophagy plays a neuroprotective or neurodegenerative role in SCIR injury remains controversial. To explore these issues, we created an SCIR injury rat model via aortic arch occlusion. Compared with normal controls, autophagic cell death was upregulated in neurons after SCIR injury. We found that autophagy promoted neuronal cell death during SCIR, shown by a significant number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling- (TUNEL-) positive cells colabeled with the autophagy marker microtubule-associated protein 1 light chain 3, while the autophagy inhibitor 3-methyladenine reduced the number of TUNEL-positive cells and restored neurological and motor function. Additionally, we showed that oxidative stress was the main trigger of autophagic neuronal cell death after SCIR injury and N-acetylcysteine inhibited autophagic cell death and restored neurological and motor function in SCIR injury. Finally, we found that hydrogen sulfide (H2S) inhibited autophagic cell death significantly by reducing oxidative stress in SCIR injury via the AKT-the mammalian target of rapamycin (mTOR) pathway. These findings reveal that oxidative stress induces autophagic cell death and that H2S plays a neuroprotective role by reducing oxidative stress in SCIR.

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Borax Partially Prevents Neurologic Disability and Oxidative Stress in Experimental Spinal Cord Ischemia/Reperfusion Injury

Journal of Stroke and Cerebrovascular Diseases ◽

10.1016/j.jstrokecerebrovasdis.2014.07.037 ◽

2015 ◽

Vol 24 (1) ◽

pp. 83-90 ◽

Cited By ~ 8

Author(s):

Emine Rabia Koc ◽

Emre Cemal Gökce ◽

Mehmet Akif Sönmez ◽

Mehmet Namuslu ◽

Aysun Gökce ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Neurologic Disability ◽

And Oxidative Stress

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Salvianolic acid B attenuates spinal cord ischemia-reperfusion–induced neuronal injury and oxidative stress by activating the extracellular signal–regulated kinase pathway in rats

Journal of Surgical Research ◽

10.1016/j.jss.2013.11.1118 ◽

2014 ◽

Vol 188 (1) ◽

pp. 222-230 ◽

Cited By ~ 20

Author(s):

Jun Fu ◽

Hong-bin Fan ◽

Zheng Guo ◽

Zhen Wang ◽

Xiang-dong Li ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Salvianolic Acid B ◽

Salvianolic Acid ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Kinase Pathway ◽

And Oxidative Stress

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Salidroside Ameliorates Mitochondria-Dependent Neuronal Apoptosis after Spinal Cord Ischemia-Reperfusion Injury Partially through Inhibiting Oxidative Stress and Promoting Mitophagy

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/3549704 ◽

2020 ◽

Vol 2020 ◽

pp. 1-22

Author(s):

Changjiang Gu ◽

Linwei Li ◽

Yifan Huang ◽

Dingfei Qian ◽

Wei Liu ◽

...

Keyword(s):

Spinal Cord ◽

Reperfusion Injury ◽

Neuronal Apoptosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Neurological Dysfunction ◽

Spinal Cord Neurons

Ischemia-reperfusion injury is the second most common injury of the spinal cord and has the risk of neurological dysfunction and paralysis, which can seriously affect patient quality of life. Salidroside (Sal) is an active ingredient extracted from Herba Cistanche with a variety of biological attributes such as antioxidant, antiapoptotic, and neuroprotective activities. Moreover, Sal has shown a protective effect in ischemia-reperfusion injury of the liver, heart, and brain, but its effect in ischemia-reperfusion injury of the spinal cord has not been elucidated. Here, we demonstrated for the first time that Sal pretreatment can significantly improve functional recovery in mice after spinal cord ischemia-reperfusion injury and significantly inhibit the apoptosis of neurons both in vivo and in vitro. Neurons have a high metabolic rate, and consequently, mitochondria, as the main energy-supplying suborganelles, become the main injury site of spinal cord ischemia-reperfusion injury. Mitochondrial pathway-dependent neuronal apoptosis is increasingly confirmed by researchers; therefore, Sal’s effect on mitochondria naturally attracted our attention. By means of a range of experiments both in vivo and in vitro, we found that Sal can reduce reactive oxygen species production through antioxidant stress to reduce mitochondrial permeability and mitochondrial damage, and it can also enhance the PINK1-Parkin signaling pathway and promote mitophagy to eliminate damaged mitochondria. In conclusion, our results show that Sal is beneficial to the protection of spinal cord neurons after ischemia-reperfusion injury, mainly by reducing apoptosis associated with the mitochondrial-dependent pathway, among which Sal’s antioxidant and autophagy-promoting properties play an important role.

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Direct Peritoneal Resuscitation with Pyruvate Protects the Spinal Cord and Induces Autophagy via Regulating PHD2 in a Rat Model of Spinal Cord Ischemia-Reperfusion Injury

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/4909103 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Ying Xiong ◽

Yun Xia ◽

Jiangtao Deng ◽

Xuetao Yan ◽

Jianjuan Ke ◽

...

Keyword(s):

Spinal Cord ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Specific Inhibitor ◽

Glucose Deprivation ◽

Signal Pathway ◽

Significant Difference

Direct peritoneal resuscitation with pyruvate (Pyr-PDS) has emerged as an interesting candidate to alleviate injury in diverse organs, while the potential mechanism has yet to be fully elucidated. To explore the effect of autophagy in the spinal cord ischemia-reperfusion (SCIR) injury and the underlying mechanism, we established a model of SCIR in vivo and in vitro. In vivo, male SD rats underwent aortic occlusion for 60 min and then followed by intraperitoneally infused with 20 mL of pyruvate or normal saline for 30 min, and the spinal cords were removed for analysis after 48 h of reperfusion. The functional and morphological results showed that Pyr-PDS alleviated SCIR injury; meanwhile, the expression of autophagy-related genes and transmission electron microscopy displayed autophagy was activated by SCIR injury, and Pyr-PDS treatment could further upregulate the degree of autophagy which plays a protective part in the SCIR injury, while there is no significant difference after treatment with saline. In addition, SCIR injury inhibited expression of PHD2, which results to activate its downstream HIF-1α/BNIP3 pathway to promote autophagy. In the Pyr-PDS, the results revealed PHD2 was further inhibited compared to the SCIR group, which could further activate the HIF-1α/BNIP3 signaling pathway. Additionally, oxygen-glucose deprivation and reoxygenation were applied to SH-SY5Y cells to mimic anoxic conditions in vitro, and the expression of autophagy-related genes, PHD2, and its downstream HIF-1α/BNIP3 pathway showed the same trend as the results in vivo. Besides, IOX2, a specific inhibitor of PHD2 was also treated to SH-SY5Y cells during reoxygenation, in which the result is as same as the pyruvate group. Then, we observed the expression of autophagy-related genes and the HIF-1α signal pathway in the process of reoxygenation; the results showed that as the reoxygenation goes, the expression of the HIF-1α signal pathway and degree of autophagy came to decrease gradually, while treated with pyruvate could maintain autophagy high and stable through keeping PHD2 at a lower level during reoxygenation, and the latter was observed downregulated during reoxygenation process from 0 to 24 hours in a time-effect way. The above results indicated that direct peritoneal resuscitation with pyruvate showed effective protection to ischemia-reperfusion of the spinal cord through activating autophagy via acting on PHD2 and its downstream HIF-1α/BNIP3 pathway.

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