Abstract WMP37: MicroRNA-29a Protects Against Cerebral Ischemia and Reperfusion Injury by Targeting NADPH Oxidase 4

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Yong-Hua Tuo ◽  
Zhong Liu ◽  
Lei Feng ◽  
Zhong-Song Shi
Keyword(s):  
Cerebral Ischemia ◽  
Nadph Oxidase ◽  
Reperfusion Injury ◽  
Blood Brain Barrier ◽  
Neurological Outcome ◽  
Infarct Volume ◽  
Brain Barrier ◽  
Ischemia And Reperfusion ◽  
Ischemia And Reperfusion Injury ◽  
Cerebral Ischemia And Reperfusion

Background: MicroRNA-29a (miR-29a) is involved in regulating cerebral ischemia process, but its underlying mechanism is unclear. We previously showed that inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4) pathway improves the neurological outcome and increases the expression of miR-29a in transient middle cerebral artery occlusion (tMCAO) animal model. This study investigated the role of miR-29a in cerebral ischemia and reperfusion injury after mechanical reperfusion. Methods: The intraluminal filament tMCAO model was established in male rats with 2 hour ischemia followed by reperfusion. The expression of miR-29a and NOX4 in the infarction core and peri-infarct cortex were quantified at 0, 3, 12, and 24 hour after reperfusion. Permanent MCAO model was also evaluated after 2 hour and 24 hour ischemia. Intravenous miR-29a agomir was delivered immediately after reperfusion. Infarct volume, brain water content, neurological score, blood-brain barrier damage, and levels of miR-29a and NOX4 were determined at 24-hour after cerebral ischemia. Results: MiR-29a levels in the infarction core and peri-infarct cortex were significantly decreased at 3 hours after reperfusion in tMCAO group compared with the sham-operated group. The decreased levels of miR-29a lasted for 24 hours after cerebral ischemia. Dual-luciferase reporter system showed that NOX4 was the direct target gene of miR-29a. Intravenous miR-29a agomir increased the expression of miR-29a and suppressed NOX4 up-regulation in both the infarction core and peri-infarct cortex at 24-hour after ischemia compared with the tMCAO group (all p<0.05). Intravenous miR-29a agomir reduced infarct volume (24.7% ± 4.0% versus 37.8% ± 7.5%, p<0.01) at 24-hour after ischemia compared to the tMCAO group. MiR-29a agomir attenuated brain edema and reduced reperfusion-induced blood-brain barrier breakdown, resulting in improved neurological outcome (all p<0.05). Conclusions: MiR-29a overexpression protects against cerebral ischemia and reperfusion injury via downregulating NOX4. Infusion of miR-29a agomir immediately after reperfusion represents a novel adjunctive therapeutic strategy to improve outcome after mechanical reperfusion for acute ischemic stroke.

scholarly journals Neuroprotective Mechanisms of Calycosin Against Focal Cerebral Ischemia and Reperfusion Injury in Rats

2018 ◽  
Vol 45 (2) ◽  
pp. 537-546 ◽  
Author(s):  
Yong Wang ◽  
Qianyao Ren ◽  
Xing Zhang ◽  
Huiling Lu ◽  
Jian Chen
Keyword(s):  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Brca1 Gene ◽  
Ischemia And Reperfusion ◽  
Ischemia And Reperfusion Injury ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia And Reperfusion ◽  
Tnf Α

Background/Aims: Emerging evidence suggests that autophagy plays important roles in the pathophysiological processes of cerebral ischemia and reperfusion injury. Calycosin, an isoflavone phytoestrogen, possesses neuroprotective effects in cerebral ischemia and reperfusion in rats. Here, we investigated the neuroprotective effects of calycosin against ischemia and reperfusion injury, as well as related probable mechanisms behind autophagy pathways. Methods: A cerebral ischemic and reperfusion injury model was established by middle cerebral artery occlusion in male Sprague-Dawley rats. Neurological scores, infarct volumes, and brain water content were assessed after 24 h reperfusion following 2 h ischemia. Additionally, the expression of the autophagy-related protein p62 and NBR1 (neighbor of BRCA1 gene 1), as well as Bcl-2, and TNF-α in rat brain tissues was measured by RT-PCR, western blotting and immunohistochemical analyses. Results: The results showed that calycosin pretreatment for 14 days markedly decreased infarct volume and brain edema, and ameliorated neurological scores in rats with focal cerebral ischemia and reperfusion. It was observed that levels of p62, NBR1 and Bcl-2 were greatly decreased, and levels of TNF-α significantly increased after ischemia and reperfusion injury. However, calycosin administration dramatically upregulated the expression of p62, NBR1 and Bcl-2, and downregulated the level of TNF-α. Conclusions: All data reveal that calycosin exerts a neuroprotective effect on cerebral ischemia and reperfusion injury, and the mechanisms maybe associated with its anti-autophagic, anti-apoptotic and anti-inflammatory action.

scholarly journals Nanoparticles for Targeted Delivery of Antioxidant Enzymes to the Brain after Cerebral Ischemia and Reperfusion Injury

2013 ◽  
Vol 33 (4) ◽  
pp. 583-592 ◽  
Author(s):  
Xiang Yun ◽  
Victor D Maximov ◽  
Jin Yu ◽  
g Zhu ◽  
Alexey A Vertegel ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Targeted Delivery ◽  
Infarct Volume ◽  
The United States ◽  
Ischemia And Reperfusion ◽  
Ischemia And Reperfusion Injury ◽  
Targeted Nanoparticles ◽  
Cerebral Ischemia And Reperfusion ◽  
The Impact

Stroke is one of the major causes of death and disability in the United States. After cerebral ischemia and reperfusion injury, the generation of reactive oxygen species (ROS) and reactive nitrogen species may contribute to the disease process through alterations in the structure of DNA, RNA, proteins, and lipids. We generated various nanoparticles (liposomes, polybutylcyanoacrylate (PBCA), or poly(lactide-co-glycolide) (PLGA)) that contained active superoxide dismutase (SOD) enzyme (4,000 to 20,000 U/kg) in the mouse model of cerebral ischemia and reperfusion injury to determine the impact of these molecules. In addition, the nanoparticles were untagged or tagged with nonselective antibodies or antibodies directed against the N-methyl-D-aspartate (NMDA) receptor 1. The nanoparticles containing SOD protected primary neurons in vitro from oxygen-glucose deprivation (OGD) and limited the extent of apoptosis. The nanoparticles showed protection against ischemia and reperfusion injury when applied after injury with a 50% to 60% reduction in infarct volume, reduced inflammatory markers, and improved behavior in vivo. The targeted nanoparticles not only showed enhanced protection but also showed localization to the CA regions of the hippocampus. Nanoparticles alone were not effective in reducing infarct volume. These studies show that targeted nanoparticles containing protective factors may be viable candidates for the treatment of stroke.

scholarly journals Alpha-Lipoic Acid Attenuates Cerebral Ischemia and Reperfusion Injury via Insulin Receptor and PI3K/Akt-Dependent Inhibition of NADPH Oxidase

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Yinhua Dong ◽  
Hongxin Wang ◽  
Zefeng Chen
Keyword(s):  
Cerebral Ischemia ◽  
Nadph Oxidase ◽  
Insulin Receptor ◽  
Reperfusion Injury ◽  
Lipoic Acid ◽  
Ischemia And Reperfusion ◽  
Alpha Lipoic Acid ◽  
Ischemia And Reperfusion Injury ◽  
Cerebral Ischemia And Reperfusion ◽  
Dependent Inhibition

Alpha-lipoic acid (ALA) has various pharmacological effects such as antioxidative, anti-inflammatory, and antiapoptotic properties. In the present study, administration of ALA (40 mg/kg, i.p.) for 3 days resulted in a significant decrease in neuronal deficit score and infarct volume and a significant increase in grip time and latency time in Morris water maze at 48 h after middle cerebral artery occlusion and reperfusion (MCAO/R) in rats. ALA also reduced the increased TUNEL-positive cells rate and the enhanced caspase-3 activity induced by MCAO/R. However, the underlying mechanisms remain poorly understood. In this study, we found that ALA could activate insulin receptor and PI3K/Akt signaling pathways, inhibit the expression and activity of NADPH oxidase, and subsequently suppress the generation of superoxide and the augment of oxidative stress indicators including MDA, protein carbonylation, and 8-OHdG. In conclusion, ALA attenuates cerebral ischemia and reperfusion injury via insulin receptor and PI3K/Akt-dependent inhibition of NADPH oxidase.

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