scholarly journals Thiamet G mediates neuroprotection in experimental stroke by modulating microglia/macrophage polarization and inhibiting NF-κB p65 signaling

2016 ◽  
Vol 37 (8) ◽  
pp. 2938-2951 ◽  
Author(s):  
Yating He ◽  
Xiaofeng Ma ◽  
Daojing Li ◽  
Junwei Hao
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Bv2 Cells ◽  
Anti Inflammatory

Inflammatory responses are accountable for secondary injury induced by acute ischemic stroke (AIS). Previous studies indicated that O-GlcNAc modification (O-GlcNAcylation) is involved in the pathology of AIS, and increase of O-GlcNAcylation by glucosamine attenuated the brain damage after ischemia/reperfusion. Inhibition of β-N-acetylglucosaminidase (OGA) with thiamet G (TMG) is an alternative option for accumulating O-GlcNAcylated proteins. In this study, we investigate the neuroprotective effect of TMG in a mouse model of experimental stroke. Our results indicate that TMG administration either before or after middle cerebral artery occlusion (MCAO) surgery dramatically reduced infarct volume compared with that in untreated controls. TMG treatment ameliorated the neurological deficits and improved clinical outcomes in neurobehavioral tests by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Additionally, TMG administration reduced the number of Iba1+ cells in MCAO mice, decreased expression of the M1 markers, and increased expression of the M2 markers in vivo. In vitro, M1 polarization of BV2 cells was inhibited by TMG treatment. Moreover, TMG decreased the expression of iNOS and COX2 mainly by suppressing NF-κB p65 signaling. These results suggest that TMG exerts a neuroprotective effect and could be useful as an anti-inflammatory agent for ischemic stroke therapy.

scholarly journals Astragaloside IV for Experimental Focal Cerebral Ischemia: Preclinical Evidence and Possible Mechanisms

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Hui-Lin Wang ◽  
Qi-Hui Zhou ◽  
Meng-Bei Xu ◽  
Xiao-Li Zhou ◽  
Guo-Qing Zheng
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Quality Score ◽  
Neurological Deficits ◽  
Study Quality ◽  
Astragaloside Iv ◽  
Anti Inflammatory

Astragaloside IV (AST-IV) is a principal component of Radix Astragali seu Hedysari (Huangqi) and exerts potential neuroprotection in experimental ischemic stroke. Here, we systematically assessed the effectiveness and possible mechanisms of AST-IV for experimental acute ischemic stroke. An electronic search in eight databases was conducted from inception to March 2016. The study quality score was evaluated using the CAMARADES. Rev Man 5.0 software was used for data analyses. Thirteen studies with 244 animals were identified. The study quality score of included studies ranged from 3/10 to 8/10. Eleven studies showed significant effects of AST-IV for ameliorating the neurological function score (P<0.05); seven studies for reducing the infarct volume (P<0.05); and three or two studies for reducing the brain water content and Evans blue leakage (P<0.05), respectively, compared with the control. The mechanisms of AST-IV for ischemic stroke are multiple such as antioxidative/nitration stress reaction, anti-inflammatory, and antiapoptosis. In conclusion, the findings of present study indicated that AST-IV could improve neurological deficits and infarct volume and reduce the blood-brain barrier permeability in experimental cerebral ischemia despite some methodological flaws. Thus, AST-IV exerted a possible neuroprotective effect during the cerebral ischemia/reperfusion injury largely through its antioxidant, anti-inflammatory, and antiapoptosis properties.

scholarly journals Neuroprotective Effect of Daidzein Extracted From Pueraria lobate Radix in a Stroke Model Via the Akt/mTOR/BDNF Channel

2022 ◽  
Vol 12 ◽  
Author(s):  
Meizhu Zheng ◽  
Mi Zhou ◽  
Minghui Chen ◽  
Yao Lu ◽  
Dongfang Shi ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Neuronal Damage ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Stroke Model ◽  
Mtor Signaling Pathway ◽  
Therapeutic Research

Daidzein is a plant isoflavonoid primarily isolated from Pueraria lobate Radix as the dry root of P. lobata (Wild.) Ohwi, have long been used as nutraceutical and medicinal herb in China. Despite the report that daidzein can prevent neuronal damage and improve outcome in experimental stroke, the mechanisms of this neuroprotective action have been not fully elucidated. The aim of this study was to determine whether the daidzein elicits beneficial actions in a stroke model, namely, cerebral ischemia/reperfusion (I/R) injury, and to reveal the underlying neuroprotective mechanisms associated with the regulation of Akt/mTOR/BDNF signal pathway. The results showed that I/R, daidzein treatment significantly improved neurological deficits, infarct volume, and brain edema at 20 and 30 mg/kg, respectively. Meanwhile, it was found out that the pretreatment with daidzein at 20 and 30 mg/kg evidently improved striatal dopamine and its metabolite levels. In addition, daidzein treatment reduced the cleaved Caspase-3 level but enhanced the phosphorylation of Akt, BAD and mTOR. Moreover, daidzein at 30 mg/kg treatment enhanced the expression of BDNF and CREB significantly. This protective effect of daidzein was ameliorated by inhibiting the PI3K/Akt/mTOR signaling pathway using LY294002. To sum up, our results demonstrated that daidzein could protect animals against ischemic damage through the regulation of the Akt/mTOR/BDNF channel, and the present study may facilitate the therapeutic research of stroke.

Abstract 1944: Atorvastatin Reduces Intracerebral Hemorrhage after Experimental Stroke

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hazem F Elewa ◽  
Anna Kozak ◽  
David Rychly ◽  
Adviye Ergul ◽  
Reginald Frye ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Intracerebral Hemorrhage ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Methyl Cellulose ◽  
The United States ◽  
Experimental Stroke ◽  
High Risk Population ◽  
Protective Agent ◽  
Oral Gavage

Ischemic stroke is a leading cause of death and disability in the United States and diabetes mellitus is the fastest growing risk factor for stroke. In addition, hyperglycemia, which is usually associated with diabetes, tends to worsen ischemia/reperfusion injury and to induce more oxidative stress damage. Preliminary data from our laboratory showed that diabetic animals (Goto-Kakizaki rats (GKs) are more susceptible to vascular damage leading to intracerebral hemorrhage. Many studies have indicated that statins possess neuroprotective properties even when administered after the onset of ischemia. However, the acute vascular effects of statins after ischemic stroke have not been studied to date. Objective: to evaluate the efficacy and magnitude of vascular protection of acute statin therapy in both GKs and their normoglycemic controls after experimental ischemic stroke. Methods: Male Wistar (W) and GK rats (270–305 g) underwent 3 hours of middle cerebral artery occlusion (MCAO) followed by reperfusion for 21 hours. Animals were randomized to receive either atorvastatin (15mg/Kg) or methyl cellulose (0.5%), administered by oral gavage, the first dose 5 minutes after reperfusion and the second dose after 12 hours. Brain tissue was analyzed for infarct volume and hemoglobin content. In another set of Wistar rats (n=3), atorvastatin (15mg/Kg) was administered by oral gavage to compare its pharmacokinetic profile with that of humans Results: Atorvastatin-treated groups had significantly lower hemoglobin (p=0.0156) and infarct volume (p=0.0132) compared to their controls. Atorvastatin peak concentration (27–77 ng/ml) in rats’ plasma was found to be similar to that seen after 80mg/day of atorvastatin in humans. Conclusion: Atorvastatin can be a novel vascular protective agent after acute ischemic stroke especially in a high risk population like diabetics. The mechanisms through which these effects are mediated are currently being investigated.

scholarly journals Anti-Inflammatory Effects of the 70 kDa Heat Shock Protein in Experimental Stroke

2007 ◽  
Vol 28 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Zhen Zheng ◽  
Jong Youl Kim ◽  
Hualong Ma ◽  
Jong Eun Lee ◽  
Midori A Yenari
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Brain Ischemia ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Artery Occlusion ◽  
Brain Inflammation ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Anti Inflammatory

The 70-kDa heat shock protein (Hsp70) is involved in protecting the brain from a variety of insults including stroke. Although the mechanism has been largely considered to be because of its chaperone functions, recent work indicates that Hsp70 also modulates inflammatory responses. To explore how and whether Hsp70 regulate immune responses in brain ischemia, mice overexpressing Hsp70 (Hsp Tg) were subjected to 2 h middle cerebral artery occlusion, followed by 24 h reperfusion. Parallel experiments were performed using a brain inflammation model. Hsp Tg microglia cocultured with astrocytes were used to evaluate the direct effects of Hsp70 on cytotoxicity of mcrigolia. Compared with wild-type (Wt) littermates, Hsp Tg mice showed decreased infarct size and improved neurological deficits. The number of activated microglia/macrophages were also reduced in ischemic brains of Hsp Tg mice. Similar observations were made in a model of brain inflammation that does not result in brain cell death. Overexpression of Hsp70 in microglia completely prevented microglia-induced cytotoxicity to astrocytes. Activation of the inflammatory transcription factor, nuclear factor-κB (NF-κB) was inhibited significantly in Hsp Tg mice and microglia. This was associated with decreased phosphorylation of NF-κB inhibitor protein, IκBα, and decreased expression of several NFκB-regulated genes. Co-immunoprecipitation studies revealed an interaction of Hsp70 with NF-κB and IκBα, but not with IkB kinase, IKKγ, suggesting that Hsp70 binds to the NF-κB:IκB complex preventing IκB phosphorylation by IKK. The findings of the present work establish an anti-inflammatory role for Hsp70 in the context of brain ischemia as a novel mechanism of protection.

scholarly journals The Role of Alpha-Lipoic Acid in the Pathomechanism of Acute Ischemic Stroke

2018 ◽  
Vol 48 (1) ◽  
pp. 42-53 ◽  
Author(s):  
Qingqing Wang ◽  
Chengmei Lv ◽  
Yongxin Sun ◽  
Xu Han ◽  
Shan Wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Lipoic Acid ◽  
Nuclear Translocation ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Phenotype

Background/Aims: Ischemic stroke results in increased cerebral infarction, neurological deficits and neuroinflammation. The underlying mechanisms involving the anti-inflammatory and neuroprotective properties of α-Lipoic acid (α-LA) remain poorly understood. Herein, we investigated the potential role of α-LA in a middle cerebral artery occlusion (MCAO) rat model and an in vitro lipopolysaccharide (LPS)-induced microglia inflammation model. Methods: In the in vivo study, infarct volume was examined by TTC staining and Garcia score was used to evaluate neurologic recovery. The cytokines were evaluated by enzyme-linked immunosorbent assay, and protein expression of microglia phenotype and NF-κB were measured using western blot. In the in vitro study, the expressions of microglia M1/M2 phenotype were evaluated using qRT-PCR, and immunofluorescence staining was used to assess the nuclear translocation of NF-κB. Results: Both 20 mg/kg and 40 mg/kg of α-LA alleviated infarct size, brain edema, and neurological deficits. Furthermore, α-LA induced the polarization of microglia to the M2 phenotype, modulated the expression of IL-1β, IL-6, TNF-α and IL-10, and attenuated the activation of NF-κB after MCAO. α-LA inhibited the expression of M1 markers, increased activation of the M2 markers, and suppressed the nuclear translocation of NF-κB in LPS-stimulated BV2 microglia. Conclusions: α-LA improved neurological outcome in experimental stroke via modulating microglia M1/M2 polarization. The potential mechanism of α-LA might be mediated by inhibition of NF-κB activation via regulating phosphorylation and nuclear translocation of p65.

scholarly journals Therapeutic Effects of Systemic Administration of the Novel RANKL-Modified Peptide, MHP1, for Ischemic Stroke in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Munehisa Shimamura ◽  
Hironori Nakagami ◽  
Hideo Shimizu ◽  
Kouji Wakayama ◽  
Tomohiro Kawano ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Volume ◽  
Brain Parenchyma ◽  
Neurological Deficits ◽  
Therapeutic Effects ◽  
Inhibitory Effects ◽  
Continuous Administration ◽  
Anti Inflammatory ◽  
Rank Signaling ◽  
Continuous Injection

Microglial healing peptide 1, “MHP1”, is a newly developed synthetic peptide composed of the DE and a part of the EF loop of the receptor activator of nuclear factor-кB (NFκB) ligand (RANKL). Our previous report demonstrated that MHP1 significantly inhibits Toll-like receptor (TLR) 2- and 4-induced inflammation in microglia/macrophages through RANK signaling without osteoclast activation. However, its inhibitory effects on ischemic stroke when administered intravenously have not been clarified. First, we examined whether MHP1 could penetrate the brain parenchyma. Intravenous injection of FITC-conjugated MHP1 demonstrated that MHP1 could cross the blood-brain-barrier in peri-infarct regions, but not in intact regions. Because MHP1 in the parenchyma was reduced at 60 minutes after injection, we speculated that continuous injection was necessary to achieve the therapeutic effects. To check the possible deactivation of MHP1 by continuous injection, the anti-inflammatory effects were checked in MG6 cells after incubation in 37°C for 24 hours. Although the inhibitory effects for IL6 and TNFα were reduced compared to nonincubated MHP1, its anti-inflammatory efficacy remained, indicating that continuous administration with pump was possible. The single and successive continuous administration of MHP1 starting from 4 or 6 hours after cerebral ischemia successfully reduced infarct volume and prevented the exacerbation of neurological deficits with reduced activation of microglia/macrophages and inflammatory cytokines. Different from recombinant RANKL, MHP1 did not activate osteoclasts in the paralytic arm. Although further modification of MHP1 is necessary for stabilization, the MHP1 could be a novel agent for the treatment ischemic stroke.

scholarly journals Neuroprotective and Anti-Inflammatory Effect of Pterostilbene Against Cerebral Ischemia/Reperfusion Injury via Suppression of COX-2

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjun Yan ◽  
Dongqing Ren ◽  
Xiaoxue Feng ◽  
Jinwen Huang ◽  
Dabin Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Inflammatory Cytokines ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Polymorphonuclear Leucocyte ◽  
The Body ◽  
Cox 2 ◽  
Anti Inflammatory

Background: The incidence of cerebral ischemia disease leading cause of death in human population worldwide. Treatment of cerebral ischemia remains a clinical challenge for researchers and mechanisms of cerebral ischemia remain unknown. During the cerebral ischemia, inflammatory reaction and oxidative stress plays an important role. The current investigation scrutinized the neuroprotective and anti-inflammatory role of pterostilbene against cerebral ischemia in middle cerebral artery occlusion (MCAO) rodent model and explore the underlying mechanism.Methods: The rats were divided into following groups viz., normal, sham, MCAO and MCAO + pterostilbene (25 mg/kg) group, respectively. The groups received the oral administration of pterostilbene for 30 days followed by MCAO induction. The neurological score, brain water content, infarct volume and Evan blue leakage were estimated. Hepatic, renal, heart, inflammatory cytokines and inflammatory mediators were estimated.Results: Pterostilbene treatment significantly (p &lt; 0.001) improved the body weight and suppressed the glucose level and brain weight. Pterostilbene significantly (p &lt; 0.001) reduced the hepatic, renal and heart parameters. Pterostilbene significantly (p &lt; 0.001) decreased the level of glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and decreased the level of malonaldehyde (MDA), 8-Hydroxy-2′-deoxyguanosine (8-OHdG). Pterostilbene significantly (p &lt; 0.001) inflammatory cytokines and inflammatory parameters such as cyclooxygenase-2 (COX-2), inducible nitric oxidase synthase (iNOS) and prostaglandin (PGE2). Pterostilbene significantly (p &lt; 0.001) down-regulated the level of metalloproteinases (MMP) such as MMP-2 and MMP-9. Pterostilbene suppressed the cellular swelling, cellular disintegration, macrophage infiltration, monocyte infiltration and polymorphonuclear leucocyte degranulation in the brain.Conclusion: In conclusion, Pterostilbene exhibited the neuroprotective effect against cerebral ischemia in rats via anti-inflammatory mechanism.

scholarly journals Exogenous hydrogen sulfide attenuates cerebral ischemia–reperfusion injury by inhibiting autophagy in mice

2016 ◽  
Vol 94 (11) ◽  
pp. 1187-1192 ◽  
Author(s):  
Mengyang Shui ◽  
Xiaoyan Liu ◽  
Yuanjun Zhu ◽  
Yinye Wang
Keyword(s):  
Hydrogen Sulfide ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Artery Occlusion ◽  
Neurological Deficits ◽  
Western Blot Assay

Hydrogen sulfide (H2S), the third gas transmitter, has been proven to be neuroprotective in cerebral ischemic injury, but whether its effect is mediated by regulating autophagy is not yet clear. The present study was undertaken to explore the underlying mechanisms of exogenous H2S on autophagy regulation in cerebral ischemia. The effects and its connection with autophagy of NaHS, a H2S donor, were observed through neurological deficits and cerebral infarct volume in middle cerebral artery occlusion (MCAO) mice; autophagy-related proteins and autophagy complex levels in the ischemic hemisphere were detected with Western blot assay. Compared with the model group, NaHS significantly decreased infarct volume and improved neurological deficits; rapamycin, an autophagy activator, abolished the effect of NaHS; NaHS decreased the expression of LC3-II and up-regulated p62 expression in the ischemic cortex 24 h after ischemia. However, NaHS did not significantly influence Beclin-1 expression. H2S has a neuroprotective effect on ischemic injury in MCAO mice; this effect is associated with its influence in down-regulating autophagosome accumulation.

scholarly journals Taurine Protects against Postischemic Brain Injury via the Antioxidant Activity of Taurine Chloramine

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 372
Author(s):  
Song-I Seol ◽  
Hyun Jae Kim ◽  
Eun Bi Choi ◽  
In Soon Kang ◽  
Hye-Kyung Lee ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Brain Injury ◽  
Antioxidant Enzyme ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Neurological Deficits ◽  
Heme Oxygenase 1 ◽  
Taurine Chloramine ◽  
Neuroprotective Effects ◽  
Bv2 Cells

Taurine is ubiquitously distributed in mammalian tissues and is highly concentrated in the heart, brain, and leukocytes. Taurine exerts neuroprotective effects in various central nervous system diseases and can suppress infarct formation in stroke. Taurine reacts with myeloperoxidase (MPO)-derived hypochlorous acid (HOCl) to produce taurine chloramine (Tau-Cl). We investigated the neuroprotective effects of taurine using a rat middle cerebral artery occlusion (MCAO) model and BV2 microglial cells. Although intranasal administration of taurine (0.5 mg/kg) had no protective effects, the same dose of Tau-Cl significantly reduced infarct volume and ameliorated neurological deficits and promoted motor function, indicating a robust neuroprotective effect of Tau-Cl. There was neutrophil infiltration in the post-MCAO brains, and the MPO produced by infiltrating neutrophils might be involved in the taurine to Tau-Cl conversion. Tau-Cl significantly increased the levels of antioxidant enzymes glutamate–cysteine ligase, heme oxygenase-1, NADPH:quinone oxidoreductase 1, and peroxiredoxin-1 in BV2 cells, whereas taurine slightly increased some of them. Antioxidant enzyme levels were increased in the post-MCAO brains, and Tau-Cl further increased the level of MCAO-induced antioxidant enzymes. These results suggest that the neutrophils infiltrate the area of ischemic injury area, where taurine is converted to Tau-Cl, thus protecting from brain injury by scavenging toxic HOCl and increasing antioxidant enzyme expression.

scholarly journals Genistein-3′-sodium Sulfonate Attenuates Cerebral Ischemia/reperfusion Injury in Rats by Down-regulating Microglial M1 Polarization Through α7nAChR-mediated Inhibition of NF-κb Signaling Pathway 

2020 ◽  
Author(s):  
Chao-Ming Liu ◽  
Song Liu ◽  
Li-Jiao Xiong ◽  
Xiao Li ◽  
Xingling Cao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Neurological Deficit ◽  
Morphological Changes ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Brain Regions ◽  
Immunofluorescent Staining ◽  
Sodium Sulfonate ◽  
Bv2 Cells

Abstract Background: Microglial M1 depolarization mediated prolonged inflammation contributing to brain injury in ischemic stroke. Our previous study revealed that Genistein-3′-sodium sulfonate (GSS) exerted neuroprotective effects in ischemic stroke and reduced pro-inflammatory cytokines production. This study aimed to explore whether GSS protected against brain injury in ischemic stroke by regulating microglial M1 depolarization and its underlying mechanisms. Methods: We established transient middle cerebral artery occlusion and reperfusion (tMCAO) model in rats and used lipopolysaccharide (LPS)-stimulated BV2 microglial cells as in vitro model. Brain infarcted volume and neurological deficit were evaluated by TTC staining and Garcia assessment, respectively. M1-depolarized markers, α7nAChR and NF-κB signaling proteins were determined using western blot. Real-time PCR was used to determine the expression of M1 depolarization markers. Morphological changes, IL-1β expression and the nucleus translocation of P65-NF-κB were measured using immunofluorescent staining. The level of IL-1β was also determined using ELISA. Results: Our results showed that GSS treatment significantly reduced the brain infarcted volume and improved the neurological function in tMCAO rats. Meanwhile, GSS treatment also dramatically reduced microglia M1 depolarization, reversed α7nAChR expression, and inhibited the activation of NF-κB signaling in the ischemic penumbra brain regions. These effects of GSS were further verified in LPS-induced M1 depolarization of BV2 cells. Furthermore, pretreatment of α7nAChR inhibitor (α-BTX) significantly restrained the neuroprotective effect of GSS treatment in both tMCAO rats and LPS-stimulated BV2 cells. Alpha-BTX also blunted the regulating effects of GSS on GSM1 depolarization and α7nAChR expression.Conclusions: This study demonstrates that GSS protects against brain injury and neurological deficit in ischemic stroke by reducing microglia M1 depolarization to suppress neuroinflammation in peri-infarcted brain regions through upregulating α7nAChR and thereby inhibition of NF-κB signaling. Our findings uncover a potential molecular mechanism for GSS treatment in ischemic stroke.

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