scholarly journals Neuroprotective Effects of Ginsenosides against Cerebral Ischemia

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1102 ◽  
Author(s):  
Zhekang Cheng ◽  
Meng Zhang ◽  
Chengli Ling ◽  
Ying Zhu ◽  
Hongwei Ren ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Neurological Dysfunction ◽  
Control Group ◽  
Protective Effects ◽  
Ginsenoside Rb1 ◽  
Neuroprotective Effects

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

scholarly journals Protective Effects of Millettia Pulchra Flavonoids on Myocardial Ischemia In Vitro and In Vivo

2015 ◽  
Vol 35 (2) ◽  
pp. 516-528 ◽  
Author(s):  
Jianchun Huang ◽  
Xudong Zhang ◽  
Feizhang Qin ◽  
Yingxin Li ◽  
Xiaoqun Duan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Myocardial Ischemia ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Protective Effects ◽  
Bax Protein ◽  
Oxide Synthase

Background: Previous studies have demonstrated that Millettia pulchra flavonoids (MPF) exhibit protective effects on myocardial ischemia reperfusion injury (MI/RI) in isolated rat hearts and show anti-oxidative, anti-hypoxic and anti-stress properties. Methods: In this study, the cardioprotective effects of MPF on myocardial ischemia and its underlying mechanisms were investigated by a hypoxia/ reoxygenation (H/R) injury model in vitro and a rat MI/RI model in vivo. Results: We found that the lactate dehydrogenase (LDH) and inducible nitric oxide synthase (iNOS) activities were decreased in the MPF pretreatment group, whereas the activities of constructional nitric oxide synthase (cNOS), total nitric oxide synthase (tNOS), Na+-K+-ATPase and Ca2+-Mg2+-ATPase were significantly increased. In addition, the cardiocytes were denser in the MPF groups than in the control group. The mortality rate and apoptosis rate of cardiocytes were significantly decreased. Furthermore, pretreatment with MPF in vivo significantly improved the hemodynamics, decreased malondialdehyde (MDA) abundance, increased the activities of plasma superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and decreased the expression of the Bax protein and ratio Bax/Bc1-2 ration. Conclusions: These results suggest that MPF is an attractive protective substance in myocardial ischemia due to its negative effects on heart rate and ionotropy, reduction of myocardial oxidative damage and modulation of gene expression associated with apoptosis.

scholarly journals Schizandrin Protects against OGD/R-Induced Neuronal Injury by Suppressing Autophagy: Involvement of the AMPK/mTOR Pathway

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3624 ◽  
Author(s):  
Guangyun Wang ◽  
Tiezheng Wang ◽  
Yuanyuan Zhang ◽  
Fang Li ◽  
Boyang Yu ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Pc12 Cells ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Mtor Pathway ◽  
Protective Effects ◽  
Compound C

The neuroprotective role of schizandrin (SA) in cerebral ischemia-reperfusion (I/R) was recently highlighted. However, whether SA plays a regulatory role on autophagy in cerebral I/R injury is still unclear. This study aimed to explore whether the neuroprotective mechanisms of SA were linked to its regulation of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/autophagy pathway in vivo and in vitro. The present study confirmed that SA significantly improved oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced PC12 cells injury. The results of immunoblotting and confocal microscope showed that SA decreased autophagy in OGD/R-injured PC12 cells, which was reflected by the decreased Beclin-1 and LC3-II expression, autophagy flux level, and LC3 puncta formation. In addition, the autophagy inducer rapamycin partially prevented the effects of SA on cell viability and autophagy after OGD/R, whereas the autophagy inhibitor 3-methyladenine (3-MA) exerted the opposite effect. The results of Western blotting showed that SA markedly decreased the phosphorylation of AMPK (p-AMPK), whereas the phosphor-mTOR (p-mTOR) levels increased in the presence of OGD/R insult. Furthermore, pretreatment with the AMPK inducer AICAR partially reversed the protective effects and autophagy inhibition of SA. However, AMPK inhibitor Compound C pretreatment further promoted the inhibition of SA on autophagy induction and cell damage induced by OGD/R. Taken together, these findings demonstrate that SA protects against OGD/R insult by inhibiting autophagy through the regulation of the AMPK-mTOR pathway and that SA may have therapeutic value for protecting neurons from cerebral ischemia.

scholarly journals Metformin Protects against Oxidative Stress Injury Induced by Ischemia/Reperfusion via Regulation of the lncRNA-H19/miR-148a-3p/Rock2 Axis

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Jing Zeng ◽  
Long Zhu ◽  
Jing Liu ◽  
Tao Zhu ◽  
Zhaohui Xie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Luciferase Reporter ◽  
Neuroprotective Effects ◽  
Stress Injury ◽  
Oxidative Stress Injury

Previous studies have shown that metformin not only is a hypoglycemic agent but also has neuroprotective effects. However, the mechanism of action of metformin in ischemic stroke is unclear. Oxidative stress is an important factor in the pathogenesis of cerebral ischemia-reperfusion injury. It has been reported that metformin is associated with stroke risk in the clinical population. This study is aimed at investigating the effect and mechanism of metformin in an experimental model of oxidative stress induced by ischemia/reperfusion (I/R) in vivo and oxygen glucose deprivation/reperfusion (OGD/R) in vitro. Metformin (100, 200, and 300 mg/kg) was administered intraperitoneally immediately after induction of cerebral ischemia. The indicators of oxidative stress selected were antioxidant enzyme activities of catalase, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), and glutathione peroxidation enzyme (GSHPx). First, we demonstrated that metformin can significantly alleviate acute and chronic cerebral I/R injury and it has a strong regulatory effect on stroke-induced oxidative stress. It can reduce the elevated activities of MDA and NO and increase the levels of GSHPx and SOD in the cerebrum of mice and N2a cells exposed to I/R. Furthermore, real-time PCR and western blot were used to detect the expression of long noncoding RNA H19 (lncRNA-H19), microRNA-148a-3p (miR-148a-3p), and Rho-associated protein kinase 2 (Rock2). The direct interaction of lncRNA-H19, miR-148a-3p, and Rock2 was tested using a dual luciferase reporter assay. lncRNA-H19 altered OGD/R-induced oxidative stress by modulating miR-148a-3p to increase Rock2 expression. The expression of lncRNA-H19 and Rock2 could be downregulated with metformin in vivo and in vitro. In conclusion, our study confirmed that metformin exerts neuroprotective effects by regulating ischemic stroke-induced oxidative stress injury via the lncRNA-H19/miR-148a-3p/Rock2 axis. These results provide new evidence that metformin may represent a potential treatment for stroke-related brain injury.

scholarly journals Niosomes of Ascorbic Acid and α-Tocopherol in the Cerebral Ischemia-Reperfusion Model in Male Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Jaleh Varshosaz ◽  
Somayeh Taymouri ◽  
Abbas Pardakhty ◽  
Majid Asadi-Shekaari ◽  
Abodolreza Babaee
Keyword(s):  
Ascorbic Acid ◽  
Cerebral Ischemia ◽  
Neuronal Damage ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Male Rats ◽  
Size Change ◽  
Neuroprotective Effects

The objective of the present study was to prepare a stableivinjectable formulation of ascorbic acid and α-tocopherol in preventing the cerebral ischemia. Different niosomal formulations were prepared by Span and Tween mixed with cholesterol. The physicochemical characteristics of niosomal formulations were evaluatedin vitro. Forin vivoevaluation, the rats were made ischemic by middle cerebral artery occlusion model for 30 min and the selected formulation was used for determining its neuroprotective effect against cerebral ischemia. Neuronal damage was evaluated by optical microscopy and transmission electron microscopy. The encapsulation efficiency of ascorbic acid was increased to more than 84% by remote loading method. The cholesterol content of the niosomes, the hydrophilicity potential of the encapsulated compounds, and the preparation method of niosomes were the main factors affecting the mean volume diameter of the prepared vesicles. High physical stability of the niosomes prepared from Span 40 and Span 60 was demonstrated due to negligible size change of vesicles during 6 months storage at 4–8°C.In vivostudies showed that ST60/Chol 35 : 35 : 30 niosomes had more neuroprotective effects against cerebral ischemic injuries in male rats than free ascorbic acid.

scholarly journals Astragali Radix Isoflavones Synergistically Alleviate Cerebral Ischemia and Reperfusion Injury Via Activating Estrogen Receptor-PI3K-Akt Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yong Gu ◽  
Xi Chen ◽  
Shuping Fu ◽  
Wenlan Liu ◽  
Qi Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neuroprotective Effects ◽  
Astragali Radix ◽  
Cerebral Ischemia Reperfusion ◽  
Cerebral Ischemia Reperfusion Injury

Isoflavones are major neuroprotective components of a medicinal herb Astragali Radix, against cerebral ischemia-reperfusion injury but the mechanisms of neuroprotection remain unclear. Calycosin and formononetin are two major AR isoflavones while daidzein is the metabolite of formononetin after absorption. Herein, we aim to investigate the synergistic neuroprotective effects of those isoflavones of Astragali Radix against cerebral ischemia-reperfusion injury. Calycosin, formononetin and daidzein were organized with different combinations whose effects observed in both in vitro and in vivo experimental models. In the in vitro study, primary cultured neurons were subjected to oxygen-glucose deprivation plus reoxygenation (OGD/RO) or l-glutamate treatment. In the in vivo study, rats were subjected to middle cerebral artery occlusion to induce cerebral ischemia and reperfusion. All three isoflavones pre-treatment alone decreased brain infarct volume and improved neurological deficits in rats, and dose-dependently attenuated neural death induced by l-glutamate treatment and OGD/RO in cultured neurons. Interestingly, the combined formulas of those isoflavones revealed synergistically activated estrogen receptor (estrogen receptors)-PI3K-Akt signaling pathway. Using ER antagonist and phosphatidylinositol 3-kinase (PI3K) inhibitor blocked the neuroprotective effects of those isoflavones. In conclusion, isoflavones could synergistically alleviate cerebral ischemia-reperfusion injury via activating ER-PI3K-Akt pathway.

scholarly journals Microglia-derived FGF21 as a modulator of astrocytic phenotype and cerebral ischemia injury

2020 ◽  
Author(s):  
Fei Liu ◽  
Dongxue Wang ◽  
Liyun Zhu ◽  
Jingting Du ◽  
Ping Lin ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Cell Counting ◽  
Fibroblast Growth Factor 21 ◽  
Protective Effects ◽  
Triphenyltetrazolium Chloride

Abstract Background: Fibroblast growth factor 21 (FGF21) is an important neuroprotective factor in the central nervous system (CNS), and it has been reported that FGF21 can protect against cerebral ischemia during the acute phase. However, the possible effects of FGF21 on ischemic brains and the interactions between FGF21 and nonneuronal cells have not been examined. Thus, the aim of this study was to elucidate the protective effects of endogenous FGF21 in ischemic brains.Methods: In this study, in vivo ischemia/reperfusion injury mouse model established by transient middle cerebral artery occlusion (MCAO)/reperfusion and in vitro cell models of oxygen/glucose deprivation (OGD)/reoxygenation (R) were used. Western blot analysis, RT-PCR, double immunofluorescence staining, immunohistochemistry, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining, neurobehavioral tests, cell counting kit-8 (CCK-8) assay and high-throughput gene sequencing were employed to explore the mechanism by which FGF21 unleash neuroprotective effort of astrocyte phenotype shifts in ischemic stroke.Results: We found that cortical FGF21 expression significantly increased after MCAO/reperfusion, peaking at 7 d. Ischemia-activated microglia were the main sources of endogenous FGF21 in brain tissue. However, FGF21 deficiency aggravated brain injury and slowed neurological functional recovery in FGF21 knockout mice. The in vitro and vivo studies revealed that FGF21 could activate astrocytes and mediate astrocytic phenotype. FGF21-activated astrocytes contributed to neuronal survival and synaptic protein upregulation after ischemia.Conclusion: Collectively, our data indicate that FGF21 plays vital roles in alleviating ischemic brain by mediating the manifestation of potentially pro-recovery astrocytic phenotypes. Therefore, modulation of FGF21 is a potential target strategy for stroke.

scholarly journals Hydroxysafflor Yellow A and Anhydrosafflor Yellow B Protect Against Cerebral Ischemia/Reperfusion Injury by Attenuating Oxidative Stress and Apoptosis via the Silent Information Regulator 1 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yijia Fangma ◽  
Huifen Zhou ◽  
Chongyu Shao ◽  
Li Yu ◽  
Jiehong Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Water Soluble ◽  
Hydroxysafflor Yellow A ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia Reperfusion ◽  
Silent Information Regulator 1

Hydroxysafflor yellow A (HSYA) and anhydrosafflor yellow B (AHSYB) are the main water-soluble compounds in Carthamus tinctorius L. However, studies on the effect of AHSYB on cerebral ischemia/reperfusion (I/R) injury and the therapeutic effect of HSYA by regulating silent information regulator 1 (SIRT1) pathway remain obscure. In this study, we investigated whether the neuroprotective effects of HSYA and AHSYB on oxygen-glucose deprivation/reoxygenation in primary-cultured hippocampal neuronal cells and the middle cerebral artery occlusion and reperfusion model in rats are associated with the regulation of the SIRT1 pathway. In vitro, HSYA and AHSYB increased cell viability, depressed oxidation properties, and reduced neuronal cell apoptosis. In vivo results showed that HSYA and AHSYB effectively reduced infarct volume, improved neurological function, suppressed apoptosis, and decreased the oxidative stress reaction. Besides, RT-PCR and Western blot analysis showed that HSYA and AHSYB increased the mRNA and protein expressions of the main factors in the SIRT1 pathway, including SIRT1, forkhead box O (FOXO) 1, and peroxisome proliferator–activated receptor coactivator 1α (PGC1α), decreased the expression of Bax, and increased the expression of Bcl-2. The results from immunohistochemistry also showed that the expressions of SIRT1, FOXO1, and PGC1α were increased after treatment with HSYA and AHSYB. Furthermore, the neuroprotective effects of HSYA and AHSYB were abolished by EX527 (SIRT1–specific inhibitor). These results indicated that HSYA and AHSYB should be developed into potential drugs for treating cerebral I/R injury via the SIRT1 pathway. Although HSYA and AHSYB have different chemical structures, both of them exert similar neuroprotective properties against I/R injury in vitro and in vivo, which means that AHSYB is also a non-negligible component in safflower.

scholarly journals Maraviroc, An Inhibitor of Chemokine Receptor Type 5, Alleviates Neuroinflammatory Response after Cerebral Ischemia/Reperfusion Injury via Regulating JNK Signaling

2021 ◽  
Author(s):  
Beilei Chen ◽  
Pingping Cao ◽  
Xin Guo ◽  
Xiaobo Li ◽  
Li Jiang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Chemokine Receptor ◽  
Ischemia Reperfusion ◽  
Primary Microglia ◽  
Neuroprotective Effects ◽  
Jnk Signaling ◽  
Cerebral Ischemia Reperfusion ◽  
Different Doses

Abstract Neuroinflammation is a key factor that contributes to the secondary injury after cerebral ischemia/reperfusion (CI/R) injury. Chemokine receptor type 5(CCR5) has shown its pro-inflammatory effects during central nervous system (CNS) diseases. However, the role of CCR5 in CI/R injury is still unclear. In this study, we administered maraviroc (MVC,APEXBIO,UK-427857), a CCR5 antagonist, to the middle cerebral artery occlusion(MCAO) mice. In vivo studies showed that MVC was successively intraperitoneally (i.p.) with different doses (5, 20, or 50 mg/kg body weight) for 3 days after mice MCAO. MVC showed its neuroprotective effects in alleviating neurological deficits and infarct volumes after MCAO. The level of apoptosis and inflammation were remarkably decreased by MVC treatment after CI/R injury. Subsequently, primary microglia were stimulated with different doses of MVC (0.2, 2, 20 or 200nM) for 12h after oxygen-glucose deprivation/reoxygenation model (OGD/R) in vitro. MVC significantly increased the viability of primary microglia after (OGD/R). The expression of pro-inflammatory cytokines (IL-1β and IL-6) in microglia were down-regulated by MVC treatment. Mechanistically, MVC also inhibited the secretion of IL-1β and IL-6 by microglia after OGD stimulation. Furthermore, the key components of NF-κB pathway were measured in vivo and in vitro after MCAO and OGD. MVC significantly inhibited the activity of NF-κB pathway in the above pathological environments. Finally, our data indicated that MVC treatment decreased the activation of JNK signaling pathway after CI/R injury in vivo and in vitro. The JNK activator anisomycin (AN，Beyotime，SC0132-5mg) reversed the neuroprotective effects of MVC, indicating that the JNK pathway is involved in the anti-inflammatory and anti-apoptotic mechanisms of MVC in CI/R injury. Our data demonstrated that CCR5 inhibition exhibits neuroprotective effects after CI/R injury. MVC, which is widely used for HIV treatment by its anti-virus effect, is a potential drug for the treatment of ischemic stroke in the future clinical trials.

Abstract WP110: TLR5 Is Related To Neuroprotective Mechanism Of Postconditioning Through NF-κB-Akt Survival Pathway In Cerebral Ischemia

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Jaewon Jeong ◽  
Jiwon Yang ◽  
Soojin Kim ◽  
Hyesun Jeong ◽  
Bokyung Kim ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Protein Interactions ◽  
Glucose Deprivation ◽  
Nuclear Accumulation ◽  
Control Group ◽  
Akt Inhibitor ◽  
Neuroprotective Effects ◽  
Survival Pathway

Background and Purpose: Although postconditioning following stroke has indicated neuroprotective mechanisms, little is known about the mechanisms that lead to neuroprotection. Using flagellin, NF-kB activators and agonists of TLR5, we tested whether TLR5 plays an integral role in NF-kB activation and postconditioning-induced neuroprotection. Method: For the postconditioning group, 30 min of MCAO was induced, then 5 min of reperfusion was performed, after which the MCA was again occluded for 5 min. Using an anaerobic chamber, bEnd.3 and BV-2 cells in the postconditioning group were subjected to 180 min OGD (oxygen and glucose deprivation) and were allowed to recover for 10 min before being subjected to 10 more min of OGD. The control group was subjected to 180 min of OGD. Flagellin, an agonist of TLR5, was used to clarify the association between TLR5 and postconditioning in vivo (ICV; 50, 100 ng/mouse) and in vitro (0.1, 0.25, 0.5, 1 ng/ ml) experiments. Immunoprecipitation and immunoblotting were used to determine the interactions of TLR5, MyD88, p-Akt, and NF-κB. Results: Animals treated with postconditioning showed significant differences in infarct volumes compared with the MCAO group up to 60.51%. Postconditioning elevated NF-κB translocation to the nuclei (p<0.001) as early as 1 hour after postconditioning following tFCI and OGD. The protein interactions and expressions of TLR5, MyD88 and p-Akt (p<0.05) were increased in in vivo and in vitro postconditioning. Additionally, inhibition of Akt phosphorylation by Akt inhibitor IV decreased NF-κB translocation after postconditioning. To clarify the role of NF-κB in postconditioning, flagellin was used as a postconditioning mimicking agent. The treatment of flagellin reduced hypoxic-ischemic injury and increased nuclear accumulation of NF-κB and activation of Akt up to 4 hr. Conclusions: Postconditioning has neuroprotective effects by activating NF-κB and Akt survival pathway under TLR5 after stroke. Agonist of TLR5, flagellin simulated NF-κB and Akt survival pathways in cerebral ischemia. Our results suggested new mechanisms of postconditioning through TLR-5 and NF-κB, which leads to the possibility of development of a postconditioning mimicking agent using NF-κB activators such as flagellin.

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