Ephedrine alleviates middle cerebral artery occlusion-induced neurological deficits and hippocampal neuronal damage in rats by activating PI3K/AKT signaling pathway

Huang, Lixian; Zhao, Bo; Li, Qunxian; Wu, Jing; Jiang, Hui; Li, Qingbin

doi:10.1080/21655979.2021.1953218

Cited by 13 publications

(7 citation statements)

References 45 publications

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“…In other words, the upregulated miR-137 promoted the phosphorylation of PI3K/Akt pathway, and INPP4B may not be the unique link bridging both of them. This also stresses a notion that all the results of bioinformatic analysis must be verified by both cell and animal experiments (33,50).…”

Section: Discussionmentioning

confidence: 77%

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LncRNA GAS5/miR-137 Is a Hypoxia-Responsive Axis Involved in Cardiac Arrest and Cardiopulmonary Cerebral Resuscitation

et al. 2022

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BackgroundCardiac arrest/cardiopulmonary resuscitation (CA/CPR) represents one of the devastating medical emergencies and is associated with high mortality and neuro-disability. Post-cardiac arrest syndrome (PCAS) is mechanistically ascribed to acute systemic ischemia/reperfusion(I/R) injury. The lncRNA/microRNA/mRNA networks have been found to play crucial roles in the pathogenesis of the hypoxia-responsive diseases. Nonetheless, the precise molecular mechanisms by which lncRNA/miRNA/mRNA axes are involved in the astrocyte–microglia crosstalk in CA/CPR have not been fully elucidated.MethodsWe collected and purified the exosomes from the blood of CA/CPR patients and supernatant of OGD/R-stimulated astrocytes. On the basis of microarray analysis, bioinformatic study, and luciferase activity determination, we speculated that lncRNA GAS5/miR-137 is implicated in the astrocyte–microglia crosstalk under the insult of systemic I/R injury. The regulation of lncRNA GAS5/miR-137 on INPP4B was examined by cellular transfection in OGD/R cell culture and by lateral ventricle injection with miR-137 agomir in CA/CPR mice model. Flow cytometry and immunofluorescence staining were performed to detect the microglial apoptosis, M1/M2 phenotype transformation, and neuroinflammation. Neurological scoring and behavior tests were conducted in CA/CPR group, with miR-137 agomir lateral-ventricle infusion and in their controls.ResultsIn all the micRNAs, miR-137 was among the top 10 micRNAs that experienced greatest changes, in both the blood of CA/CPR patients and supernatant of OGD/R-stimulated astrocytes. Bioinformatic analysis revealed that miR-137 was sponged by lncRNA GAS5, targeting INPP4B, and the result was confirmed by Luciferase activity assay. qRT-PCR and Western blotting showed that lncRNA GAS5 and INPP4B were over-expressed whereas miR-137 was downregulated in the blood of CA/CPR patients, OGD/R-stimulated astrocytes, and brain tissue of CA/CPR mice. Silencing lncRNA GAS5 suppressed INPP4B expression, but over-expression of miR-137 negatively modulated its expression. Western blotting exhibited that PI3K and Akt phosphorylation was increased when lncRNA GAS5 was silenced or miR-137 was over-expressed. However, PI3K and Akt phosphorylation was notably suppressed in the absence of miR-137, almost reversing their phosphorylation in the silencing lncRNA GAS5 group. Then we found that GAS5 siRNA or miR-137 mimic significantly increased cell viability and alleviated apoptosis after OGD/R injury. Furthermore, over-expression of miR-137 attenuated microglial apoptosis and neuroinflammation in CA/CPR mice model, exhibiting significantly better behavioral tests after CA/CPR.ConclusionLncRNA GAS5/miR-137 may be involved in the astrocyte–microglia communication that inhibits PI3K/Akt signaling activation via regulation of INPP4B during CA/CPR.

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Section: Discussionmentioning

confidence: 77%

“…The standard Western blot method was based on the previous literature ( 33 ). Hippocampus tissues or cultured cells were quickly dissected out on ice, and lysed in radioimmuno-precipitation assay (RIPA) buffer.…”

Section: Methodsmentioning

confidence: 99%

LncRNA GAS5/miR-137 Is a Hypoxia-Responsive Axis Involved in Cardiac Arrest and Cardiopulmonary Cerebral Resuscitation

et al. 2022

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“…The PI3K-Akt signaling pathway has been proposed to modulate diverse biological processes and plays a key role in podocyte apoptosis, which is connected with the progress of proteinuria and renal function [ 51 ]. It has been reported that EH exerts anti-inflammatory and antioxidative stress effects through promoting the phosphorylation of PI3K and AKT proteins [ 52 ]. As the main component of EH, quercetin has been proved to improve renal fibrosis and apoptosis in chronic renal failure rats, as well as reducing water retention and toxin accumulation by inhibiting the PI3k/Akt pathway through targeting PIK3R [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Potential Molecular Mechanisms of Ephedra Herb in the Treatment of Nephrotic Syndrome Based on Network Pharmacology and Molecular Docking

Yao

Wang

Han

et al. 2022

BioMed Research International

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Objective. To explore the possible mechanisms of Ephedra herb (EH) in the treatment of nephrotic syndrome (NS) by using network pharmacology and molecular docking in this study. Methods. Active ingredients and related targets of EH were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and the gene names corresponding to the proteins were found through the UniProt database. Then, target genes related to NS were screened out from GeneCards, PharmGKB, and OMIM databases. Next, the intersection targets were obtained successfully through Venn diagram, which were also seen as key target genes of EH and NS. Cytoscape 3.9.0 software was used to construct the effective “active ingredient-target” network diagram, and “drug-ingredient-target-disease (D-I-T-D)” network diagram. After that, the STRING database was used to construct a protein-protein interaction (PPI) network. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment involved in the targets were performed by the DAVID database and ClueGO plugin in Cytoscape. Finally, AutoDockTools software was used for molecular docking to verify the binding strength between main active ingredients and key target proteins. Results. A total of 22 main active ingredients such as quercetin, kaempferol, luteolin, and naringenin were obtained, which could act on 105 targets related to NS. Through PPI network, 53 core targets such as AKT1, TNF, IL6, VEGFA, and IL1B were found, which might play a crucial role in the treatment of NS. Meanwhile, these targets were significantly involved in PI3K-Akt signaling pathway, TNF signaling pathway, AGE-RAGE signaling pathway, hepatitis B, and pathways in cancer through GO and KEGG enrichment analysis. The docking results indicated that active ingredients such as kaempferol, luteolin, quercetin, and naringenin all had good binding to the target protein AKT1 or TNF. Among them, luteolin and naringenin binding with AKT1 showed the best binding energy (-6.2 kcal/mol). Conclusion. This study indicated that the potential mechanism of EH in treating NS may be related to PI3K-Akt signaling pathway, TNF signaling pathway, and AGE-RAGE signaling pathway, which provided better approaches for exploring the mechanism in treating NS and new ideas for further in vivo and in vitro experimental verifications.

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“…Briefly, cells were mixed with 0.25 mg/ml MTT (Sigma-Aldrich, Missouri, USA) at 37°C for 3 h, and the medium was removed, followed by adding the dimethyl sulfoxide (DMSO) for the production of blue formazan. Lastly, the OD value at 630 nm was measured by the microplate reader (Mindray, Shenzhen, China) [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

The protective effects of Pimavanserin against cerebral ischemia-induced brain injury

Tian

2021

Bioengineered

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The integrity of the blood-brain barrier (BBB) is mainly maintained by the brain vascular endothelial cells and the tight junctions amongst them. Pimavanserin is a novel agent approved for the treatment of Parkinson’s disease and exerts neuroprotective properties. The present study aims to explore the possibility that Pimavanserin might be an effective agent used for the treatment of cerebral ischemia stroke. Middle cerebral artery occlusion (MCAO) was established in mice, and oxygen-glucose deprivation/reoxygenation (OGD/R) was established in brain bEND.3 endothelial cells. Mice were randomly divided into four groups: (1) Sham operation group; (2). Pimavanserin (1 mg/kg); (3). MCAO; (4). Pimavanserin+ MCAO. We found that compared to the Sham group, the elevated neurological deficit score and brain water content increased production of inflammatory factors, increased BBB permeability, and downregulated Claudin 5 expression were observed in the MCAO group and were all dramatically reversed by the administration of Pimavanserin. Brain bEND.3 endothelial cells were treated with Pimavanserin before the exposure to OGD/R. The significantly increased lactate dehydrogenase (LDH) release, declined cell viability, increased endothelial permeability, downregulated Claudin 5 and Krüppel-like factors 6 (KLF6) were observed in the OGD/R group and were all reversed by the introduction of Pimavanserin. Lastly, the effects of Pimavanserin on the expression level of Claudin 5 and endothelial permeability in OGD/R-challenged endothelial cells were both abolished by the knockdown of KLF6. Taken together, our data revealed that Pimavanserin protected against cerebral ischemia injury by regulating the BBB integrity in a KLF6-dependent manner.

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Ephedrine alleviates middle cerebral artery occlusion-induced neurological deficits and hippocampal neuronal damage in rats by activating PI3K/AKT signaling pathway

Cited by 13 publications

References 45 publications

LncRNA GAS5/miR-137 Is a Hypoxia-Responsive Axis Involved in Cardiac Arrest and Cardiopulmonary Cerebral Resuscitation

LncRNA GAS5/miR-137 Is a Hypoxia-Responsive Axis Involved in Cardiac Arrest and Cardiopulmonary Cerebral Resuscitation

Potential Molecular Mechanisms of Ephedra Herb in the Treatment of Nephrotic Syndrome Based on Network Pharmacology and Molecular Docking

The protective effects of Pimavanserin against cerebral ischemia-induced brain injury

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