Abstract 13107: Nitroglycerin Pretreatment Induces Metabolic Tolerance to Spinal Cord Ischemia-reperfusion Injury Through Nitric Oxide-mediated Mitochondrial Katp Channel Activation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yuki Ikeno ◽  
Christian V Ghincea ◽  
Gavriel Roda ◽  
Linling Cheng ◽  
Muhammad Aftab ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Reperfusion Injury ◽  
Motor Function ◽  
Katp Channel ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Channel Activation ◽  
Mitochondrial Katp Channel

Introduction: Pharmacologic induction of metabolic tolerance to spinal cord ischemia-reperfusion injury (SCI) after thoracoabdominal aortic intervention is not well established. We previously demonstrated that nicorandil pretreatment preserved motor function in a murine SCI model via direct mitochondrial ATP-sensitive potassium (KATP) channel activation and nitric oxide (NO) donation. However, the independent role of NO-mediated neuroprotection has not been elucidated. Hypothesis: Nitroglycerin pretreatment will induce neuroprotection through NO-mediated KATP channel activation. Methods: SCI was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Pretreatment constituted intraperitoneal injection 3 consecutive days before injury. Experimental groups: sham (no pretreatment or ischemia, n=10), SCI control (normal saline, n=20), nitroglycerin 1 mg/kg (n=18), nitroglycerin 1 mg/kg + 5-hydroxydecanonate 5 mg/kg (5HD, mitochondrial KATP channel blocker, n=13), 5HD 5 mg/kg (n=10), nitroglycerin 1 mg/kg + carboxy-PTIO (cPTIO) 1 mg/kg (NO scavenger, n=16), and cPTIO 1 mg/kg (n=10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated. Results: Compared to SCI control, motor function was significantly preserved in the nitroglycerin pretreatment group at every time point after ischemia. In the nitroglycerin+5HD and nitroglycerin+cPTIO groups, motor preservation was significantly attenuated compared to nitroglycerin pretreatment (p<0.001). Histological analysis showed significant neuron preservation in the nitroglycerin pretreatment group compared with SCI control (p=0.011). This preservation was completely attenuated with 5HD or cPTIO co-administration (p=0.001). Conclusions: Nitroglycerin pretreatment significantly preserved motor function in a murine SCI model through NO-mediated KATP channel activation.

Fe3O4 methylprednisolone plus calpain inhibitor protects against spinal cord ischemia-reperfusion injury in rats

2020 ◽  
Vol 10 (9) ◽  
pp. 1554-1559
Author(s):  
Liming Wang ◽  
Xiangxing Ma ◽  
Lili Zhang ◽  
Liwei Wang
Keyword(s):  
Spinal Cord ◽  
Reperfusion Injury ◽  
Motor Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Calpain Inhibitor ◽  
Sham Operation ◽  
Model Group ◽  
Mda Content

To investigate the neuroprotective effects of pretreatment with Fe3O4 methylprednisolone plus calpain inhibitor against spinal cord ischemia-reperfusion injury (SCI) in rats. A total of 18 male Sprague Dawley rats were randomly divided into sham operation, model, and pretreatment + SCI groups (receiving 25 mg/kg Fe3O4 methylprednisolone plus calpain inhibitor) (n = 6 each). The SCI model was established by clamping the left renal inferior abdominal aorta. Hindlimb motor function was evaluated 6, 12, 24, and 48 hours after reperfusion. At 48 hours after reperfusion, spinal cord tissues were collected for histopathological examination, measurement of oxidation product accumulation (malondialdehyde, MDA), and antioxidant enzyme activity assays [superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX)]. Motor function scores were compared using non-parametric rank sum (Kruskal-Wallis) test, and mean tissue MDA content and antioxidant enzyme activities were compared using one-way analysis of variance. Compared with the sham operation group, the model group showed significantly increased MDA content (2.95 vs. 5.90 g mg; P = 0.023); significantly increased GSH-Px activity (0.31 vs. 0.78 U/mg; P = 0.001); significantly decreased SOD (16.03 vs. 8.37 U/mg; P = 0.001) and CAT (1.24 vs. 0.54 U/mg; P = 0.002) activities; and significantly decreased hindlimb motor function score at 6 hours (21 to 15.5; P =0.001). Compared with the model group, the pretreatment + SCI group showed significantly decreased MDA content (5.90 vs. 3.27 mg; P = 0.0355); significantly decreased GSH-Px activity (0.78 vs. 0.36 U/mg; P = 0.001); and significantly increased SOD (8.37 vs. 14.79 U/mg; P = 0.001) and CAT (0.54 vs. 0.89 U/mg; P = 0.043) activities. Histopathological changes were significantly less severe in the pretreatment + SCI group than in the model and sham operation groups (P < 0.05). Pretreatment with Fe3O4 methylprednisolone plus calpain inhibitor can prevent SCI by improving the balance between oxidation and antioxidant systems.

Exosome miR-23a-3p From Osteoblast Alleviates Spinal Cord Ischemia/Reperfusion Injury by Down-regulating KLF3-activated CCNL2 Transcription

2021 ◽  
Author(s):  
Cheng Wu ◽  
Qinghua Zhu ◽  
Yi Yao ◽  
Zhaoyang Shi ◽  
Chaojie Jin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Reperfusion Injury ◽  
Regulatory Mechanism ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Neurological Dysfunction ◽  
Aneurysm Surgery ◽  
Aortic Aneurysm Surgery ◽  
Geo Database

Background: Spinal cord ischemia/reperfusion injury (SCIRI) is usually caused by spinal surgery or aortic aneurysm surgery and can eventually lead to paralysis or paraplegia and neurological dysfunction. Exosomes are considered as one of the most promising therapeutic strategies for SCIRI as they can pass the blood-spinal barrier. Previous studies have proved that exosomes secreted by osteocytes have a certain slowing effect on SCIRI. Aim: We aimed to explore the effect of osteoblast secreted exosomes on SCIRI. Methods: Firstly, neurons and osteoblasts were co-cultured under different conditions. GEO database was utilized to detect the expression of miR-23a-3p in osteoblast exosomes. SCIRI cells were treated with exosomes, and the detection was taken to prove whether miR-23a-3p could slow the progression of SCIRI. Downstream gene and the potential regulatory mechanism were explored through database and functional experiments. Results: MiR-23a-3p was highly expressed in exosomes and it slowed down the process of SCIRI. Downstream mRNA KLF3 could bind to miR-23a-3p and was highly expressed in IRI. Moreover, CCNL2 was regulated by KLF3 and was highly expressed in IRI. Rescue experiments verified that miR-23a-3p suppressed the transcription of CCNL2 by targeting KLF3. Conclusion: Exosome miR-23a-3p from osteoblast alleviates SCIRI by down-regulating KLF3-activated CCNL2 transcription.

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