scholarly journals Combination of Ginsenoside Rg1 and Bone Marrow Mesenchymal Stem Cell Transplantation in the Treatment of Cerebral Ischemia Reperfusion Injury in Rats

2015 ◽  
Vol 37 (3) ◽  
pp. 901-910 ◽  
Author(s):  
Cuifen Bao ◽  
Yan Wang ◽  
Heming Min ◽  
Miaomiao Zhang ◽  
Xiaowei Du ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Cell Apoptosis ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ginsenoside Rg1 ◽  
Brain Water Content ◽  
Treatment Efficiency ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Brain Water

Background/Aims: The present study aims to explore the protective role and mechanism of ginsenoside Rg1 combined with bone marrow mesenchymal stem cell (BMSC) transplantation for cerebral ischemia reperfusion injury (CIRI) in rat brain. Methods: One hundred twenty male SD rats were randomly divided into a sham group, an Ischemia Reperfusion (IR) group, an IR group treated with BMSC transplantation (IR+BMSCs), an IR group treated with Rg1 (IR+Rg1), and an IR group treated with BMSC transplantation and Rg1 (IR+Rg1+BMSCs). To establish a CIRI model, right middle cerebral artery embolization was used. The neurological score, 2,3,5-triphenyltet-razolium chloride monohydrate (TTC) staining and brain water content were detected to assess the treatment efficiency. HE staining and TUNEL were used to explore the pathologic changes and apoptosis. To explore the protein levels of neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP), immunofluoresence was utilized. Western blotting was used to explore apoptosis-related proteins such as Bcl-2 and Bax. Results: Compared with the sham group, the IR group demonstrated obvious ischemic changes, such as significant neurologic defects and enhanced brain water content. The Rg1 treatment resulted in an obvious decrease in cell apoptosis and improved ischemic conditions. By BMSC transplantation, the transplanted cells could be differentiated into neurons and glial cells, which also improved cerebral ischemia. More importantly, the IR+Rg1+BMSCs group showed the best treatment efficiency with reduced cell apoptosis and better cerebral recovery. Conclusions: The Rg1 treatment resulted in an obvious decrease in cell apoptosis, while the transplanted cells could be differentiated into neurons and glial cells, which also improved cerebral ischemia.

Abstract 2473: Ubiquitin Ligase Huwe1 Modulates Prongf/p75ntr In Monkey Cerebral Ischemia-reperfusion Injury

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Qian G He ◽  
Lihua Yu ◽  
Wenming Xu ◽  
Jiachuan Duan ◽  
Jian Guo ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Ubiquitin Ligase ◽  
Cell Apoptosis ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Model Group ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

Background: Ischemic neuronal cell apoptosis is a principal neuropathological feature of stroke. The p75 neurotrophin receptor (p75NTR) induces apoptosis associated with JNK-p53-BAX pathway, p53 is the substrate of the HECT domain-containing E3 ubiquitin ligase Huwe1. Recent studies suggest that the precursor form of NGF (proNGF) binds to p75NTR, and withhold the interaction of proNGF/p75NTR is efficacious in reducing neuronal apoptosis. Studies on tumor and phylogeny, show that Huwe1 highly expressed in CNS, playing a role in the regulation of cell apoptosis and a variety of injury types. Our aim is to examine whether Huwe1 modulates proNGF/p75NTR in cerebral ischemia-reperfusion injury. Methods: Eight male rhesus monkey were randomly divided into two groups: sham(n=2) and model group(n=6). The model group was administered equal volume of PBS, or silencing huwe1 Lentiviral Vector or empty Vector in right caudatum and putamen using brain stereotaxic technology and subjected to transient right middle cerebral artery occlusion (MCAO) a month later. A battery of neurological evaluation and magnetic resonance imaging (MRI) were employed to evaluate animals. Animals were sacrificed 3 days after MCAO and brains were processed for testing transfection efficiency using GFP fluorescence and evaluating cell apoptosis using TUNEL staining. The related factors in caudatum, putamen, temporal lobe and hippocampus was analyzed with QPCR, western blotting with loading control GADPH, and Immunohistochemistry. Results: The model group showed significant functional deficit than sham group with neurological evaluation (p<0.05), whereas the silencing Huwe1 group’s was the most serious. In right caudatum and putament, ischemia-reperfusion injury increased the number of TUNEL+cells(p<0.05 vs sham group) and upregulation of huwe1, proNGF and p75NTR in protein and nucleotides level (p<0.05 vs sham group), but silencing Huwe1 group increased TUNEL+cells most significantly, produced profound modulation with decreased expression of Huwe1 and obvious upregulation of proNGF and p75NTR(p<0.05 vs PBS or empty Vector group) ( Figure 1 ). However, there is no significant difference in other positions (data not show). Conclusions: Huwe1 modulates proNGF/p75NTR in the cerebral ischemia-reperfusion injury, and p53 may be as a indirect fator involved in this process. Our findings provide a novel mechanism in regulating proNGF/p75NTR signaling, suggesting its potential therapeutic target in ischemic stroke.

scholarly journals Molecular mechanisms for NG-nitro-L-arginine methyl ester action against cerebral ischemia–reperfusion injury-induced blood–brain barrier dysfunction

2014 ◽  
Vol 8 (2) ◽  
pp. 173-184
Author(s):  
Hanghui Wang ◽  
Yixin Song ◽  
Dingjun Hao ◽  
Lianfang Du
Keyword(s):  
Electron Microscope ◽  
Cerebral Ischemia ◽  
Methyl Ester ◽  
Evans Blue ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Brain Water Content ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Brain Water

Abstract Background: Ischemic stroke, an acute neurological injury lacking an effective therapy, is a leading cause of death worldwide. The unmet need in stroke research is to identify viable therapeutic targets and to understand their interplay during cerebral ischemia-reperfusion (I/R) injury. Objective: To explore the protective effects and molecular mechanism of NG-nitro-L-arginine methyl ester (L-NAME) in cerebral ischemia-reperfusion injury-induced blood-brain barrier (BBB) dysfunction. Methods: Two hundred fifty-six rats were randomly assigned to a sham operation group, I/R group, and I/R with L-NAME treatment group. Brain water content was determined by calculating dry/wet weight. The permeability of the BBB was observed using an electron microscope and by determining the Evans Blue leakage from brain tissue on the ischemic side. The expression of brain MMP-9 and GFAP was determined using an immunohistochemical method. The expression of ZO-1 protein was determined by western blotting. Results: We found that L-NAME remarkably attenuated the permeability of the BBB after I/R as assessed by Evans Blue leakage and brain water content (p < 0.05). This was further confirmed by examination of the ultrastructural morphology of the BBB using a transmission electron microscope. Furthermore, we found that expression of the zonae occludens-1 (ZO-1) was decreased in endothelial cells, and expression of MMP-9 and GFAP was increased in the basement membrane and astrocyte end-feet in vehicle control groups, respectively, but these changes could be prevented by L-NAME pretreatment. Conclusion: These results suggested that the neuroprotective effects of L-NAME against BBB damage induced by I/R might be related to the upregulation of tight junction proteins and inhibition of MMP-9 and GFAP expression. L-NAME can be used as a potential MMP-9-based multiple targeting therapeutic strategy in cerebral I/R injury.

Abstract TP268: Huwe1 Is Neuroprotective Against Monkey Cerebral Ischemia-reperfusion Injury By Regulating P53- And Mcl1- Dependent Apoptotic Pathways

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Lihua Yu ◽  
Jian Guo ◽  
Guoqian He ◽  
Jingjing Zhang ◽  
Ning Chen ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Therapeutic Target ◽  
Sham Group ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Empty Vector ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury ◽  
Neural Apoptosis

Background: Neural cell apoptosis is one of the dominated mechanisms of cerebral ischemia-reperfusion injury (IRI). Anti-apotosis factor Mcl1 and apotosis factor p53 have been confirmed to play crucial roles in the apoptotic regulation previously. Mcl1 and p53 are the substrates of the ubiquitin ligases Huwe1, and which has been suggested as a potent therapeutic target in regulating cell apoptosis. Our aim is to explore whether Huwe1 modulates neural apoptosis by degrading Mcl1, p53 in cerebral ischemia-reperfusion injury. Methods: Eight health male adult rhesus monkeys were recruited in our study and were randomly devided into four groups: sham, PBS, siRNA silencing Huwe1 lentiviral vector and empty vector group. Except the sham group, the other groups were received corespondant intracranial injections and transient right middle cerebral occlusion (MCAO). A series of neurological evaluation and MRI were ulitized to evaluate animals. GFP flurescence was used to test transfection efficiency and apoptosis was detected by TUNEL staining. The expression level of related factors in causatum, putamen, temporal lobe and hippocampus were analyzed with western blot, QPCR, and immunohistochemistry. Results: The neurological deficit was much more serious in the silencing Huwe1 group than both empty vector and PBS group. The expression of Huwe1, Mcl1 and P53 were appeared a tendency to upregulate in the right caudatum and putament in model group than sham group in both protein and nucleotides level. Moreover, the number of apoptosis cells tested by TUNEL was the highest in the silencing Huwe 1 group, induced by decreasing expression of Huwe1 and obviously upragulating P53 expression. However, none of them has significant difference in other remote positions. Conclusion: Our study provides a potential novel mechnism that Huwe1 palys an important role in regulating neural apoptosis by regadading Mcl1 and P53 in cerebral IRI. In addition, for the first time, we confirm that the anti-apoptosis factor Mcl1 engages in the pathogenesis of cerebral IRI. It is possible that Huwe1 can be a potential therapeutic target for cerebral ischemia.

scholarly journals Sufentanil alleviates cerebral ischemia-reperfusion injury by inhibiting inflammation and protecting the blood-brain barrier in rats

2022 ◽  
Vol 66 (1) ◽  
Author(s):  
Zhen Wang ◽  
Xiaoyan Du ◽  
Daoyang Yu ◽  
Yang Yang ◽  
Gaoen Ma ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Brain Tissue ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Collagen Iv ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

Stroke is a brain system disease with a high fatality rate and disability rate. About 80% of strokes are ischemic strokes. Cerebral ischemia-reperfusion injury (CIRI) caused by ischemic stroke seriously affects the prognosis of stroke patients. The purpose of this study is to investigate the effect of sufentanil (SUF) on CIRI model rats. We used middle cerebral artery occlusion (MCAO) to make the CIRI model in rats and monitored region cerebral blood flow (rCBF) to ensure that blood flow was blocked and recanalized. We used ELISA and RT-PCR to detect the expression of inflammatory factors in rat serum and brain tissue. In addition, we detected the expression of metalloproteinase (MMP) 2, MMP9 and collagen IV in brain tissues and performed Evans blue (EB) assay to determine the permeability of the blood-brain barrier (BBB). Finally, we clarified the apoptosis of brain tissue through the TUNEL staining and the detection of caspase3, Bcl2 and Bax. Various concentrations of SUF, especially 5, 10 and 25 μg/kg of SUF, all alleviated the infarct size, neurological function and brain edema of MCAO rats. SUF pretreatment also effectively reduced the expression of inflammatory cytokines in MCAO rats, including interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α. In addition, SUF also inhibited MMP2 and MMP9 and promoted the expression of collagen IV, indicating that SUF attenuated the destruction of the BBB. SUF also inhibited caspase3 and Bax rats and promoted Bcl2 in MCAO rats, thus inhibiting cell apoptosis. SUF pretreatment effectively improved the neurological function and cerebral infarction of MCAO rats, inhibited excessive inflammation in rats, protected the BBB, and inhibited cell apoptosis in brain tissue.

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