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

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

Cells ◽

10.3390/cells8111370 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1370 ◽

Cited By ~ 2

Author(s):

Kim ◽

Cho ◽

Jung ◽

Yoo ◽

Oh ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Neuronal Damage ◽

Binding Protein ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Prostaglandin F2α ◽

Proteomic Approach ◽

Phosphatidylethanolamine Binding Protein

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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OP-291 NEUROPROTECTIVE EFFECT OF ATORVASTATIN ON SPINAL CORD ISCHEMIA-REPERFUSION INJURY

International Journal of Cardiology ◽

10.1016/s0167-5273(12)70186-9 ◽

2012 ◽

Vol 155 ◽

pp. S75

Author(s):

N. Çolak ◽

Y. Nazli ◽

M.F. Alpay ◽

S. Uysal ◽

A.K. Uzunlar ◽

...

Keyword(s):

Spinal Cord ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia

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The Neuroprotective Effect of Syringic Acid on Spinal Cord Ischemia/Reperfusion Injury in Rats

Inflammation ◽

10.1007/s10753-015-0177-2 ◽

2015 ◽

Vol 38 (5) ◽

pp. 1969-1978 ◽

Cited By ~ 21

Author(s):

Mehmet Tokmak ◽

Yasemin Yuksel ◽

Muserref Hilal Sehitoglu ◽

Mustafa Guven ◽

Tarik Akman ◽

...

Keyword(s):

Spinal Cord ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Syringic Acid

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935. Neuroprotective Effect of Caspase 3 Inhibition on Functional Recovery after Spinal Cord Ischemia-Reperfusion Injury in Rats

Molecular Therapy ◽

10.1016/s1525-0016(16)39293-0 ◽

2009 ◽

Vol 17 ◽

pp. S357

Keyword(s):

Spinal Cord ◽

Reperfusion Injury ◽

Functional Recovery ◽

Caspase 3 ◽

Ischemia Reperfusion Injury ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia

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Neuroprotective effect of a new free radical scavenger HL-008 against ischemia-reperfusion injury

10.21203/rs.3.rs-123994/v1 ◽

2020 ◽

Author(s):

Yahong Liu ◽

Ying Cheng ◽

Wei Zhang ◽

Hongqi Tian

Keyword(s):

Oxidative Stress ◽

Reperfusion Injury ◽

Brain Tissue ◽

Cell Activation ◽

Ischemia Reperfusion Injury ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Critical Role ◽

Radical Scavenger

Abstract Oxidative stress plays a critical role in cerebral ischemia-reperfusion injury. We previously developed a powerful antioxidant, HL-008, and this study aimed to investigate the neuroprotective function of HL-008. The in vitro and in vivo efficacy of HL-008 was evaluated using a PC-12 cell oxidative stress model induced by hydrogen peroxide and a rat model of middle cerebral artery occlusion, respectively. The MTT assay was used to analyze cell viability. TTC staining, HE staining, immunofluorescence, western blot, and proteomics were used to evaluate the infarction volume, brain tissue morphology, apoptosis, inflammation, and related pathways. Indicators related to oxidative levels were mainly detected using commercial kits. HL-008 significantly reduced the cerebral infarction area induced by ischemia-reperfusion, improved the neurological score, alleviated oxidative stress and inflammation in the brain tissue, reduced glial cell activation, inhibited brain tissue apoptosis by influencing multiple signaling pathways, and had a neuroprotective effect. If HL-008 is successfully developed, it can significantly improve the quality of life of stroke patients.

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Downregulation of Long Noncoding RNA TUG1 Attenuate MTDH /NF-κB/IL-1β mediated inflammatory damage via Targeting miR-29b-1-5p After Spinal cord ischemia reperfusion in rats

10.21203/rs.2.24618/v1 ◽

2020 ◽

Author(s):

Hui Jia ◽

Zhe Li ◽

Bo Fang ◽

Yi Chang ◽

Yongjian Zhou ◽

...

Keyword(s):

Spinal Cord ◽

Motor Function ◽

Noncoding Rna ◽

Ischemia Reperfusion Injury ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Spinal Cord Ischemia ◽

Luciferase Reporter ◽

Inflammatory Damage ◽

Blood Spinal Cord Barrier

Abstract Background: Spinal cord ischemia reperfusion (IR) is associated with an inflammatory response. The long non-coding RNA (lncRNA) taurine upregulated gene 1 (TUG1) and microRNA-29b (miR-29b) family are frequently dysregulated in neuro-ischemic diseases. However, their potential roles in spinal cord IR injury (IR) are unknown. Methods: A spinal cord IR model was established in rats by14-minute occlusion of aortic arch. The aberrant miRNAs were identified by microarray analysis, and qRT-PCR was used to validate the lncRNA and microRNA levels. The motor function of the differentially-treated animals was assessed by Tarlov scores, and the leakage of Blood-spinal cord barrier (BSCB) was measured in terms of the extravasation of Evans blue (EB) dye. The expression levels of different proteins were analyzed by Western blotting and immunofluorescence. The interaction between TUG1 and miR-29b-1-5p, TRIL and miR-29b-1-5p, and MTDH and miR-29b-1-5p were determined using bioinformatics programs and the dual-luciferase reporter assay. Results: MiR-29b-1-5p was significantly downregulated and TUG1 was upregulated in the spinal cord of rats after IR. In addition, TRIL and MTDH protein levels were also significantly increased after IR. MTDH was predicted as a target of miR-29b-1-5p and its knockdown downregulated NF-κB and IL-1β levels. In addition, a direct interaction was observed between TUG1 and miR-29b-1-5p, and knocking down TUG1 upregulated the miRNA. Furthermore, overexpression of miR-29b-1-5p or TUG1 knockdown alleviated BSCB leakage and improved hind-limb motor function, and downregulated MTDH and its downstream pro-inflammatory cytokines. Suppression of miR-29b-1-5p reversed the neuroprotective effect of TUG1 knockdown, restored the levels of MTDH/ NF-κB/IL-1β and activated astrocytes. Conclusion: Downregulation of TUG1 alleviated MTDH/NF-κB/IL-1β pathway-mediated inflammatory damage after IR by targeting miR-29b-1-5p. Keywords: Spinal cord ischemia reperfusion injury, Neuroinflammation, Blood-spinal cord barrier, Astrocytes, TUG1, miR-29b-1-5p, MTDH

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