scholarly journals A New NF-κB Inhibitor, MEDS-23, Reduces the Severity of Adverse Post-Ischemic Stroke Outcomes in Rats

2021 ◽  
Vol 12 (1) ◽  
pp. 35
Author(s):  
Elina Rubin ◽  
Agnese C. Pippione ◽  
Matthew Boyko ◽  
Giacomo Einaudi ◽  
Stefano Sainas ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Artery Occlusion ◽  
Brain Inflammation ◽  
Neurological Deficits ◽  
Stroke Outcomes ◽  
Post Stroke ◽  
Factor Α ◽  
Cerebral Artery Occlusion ◽  
First Time

Aim: Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats. Main methods: Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments. Key findings: MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α. Significance: These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke.

scholarly journals Antineuroinflammatory effects of dl-3-n-butylphthalide conferred by stimulation of Foxp3 and Ki-67 in an ischemic stroke model

2020 ◽  
Author(s):  
Xi Liu ◽  
Runzhe Liu ◽  
Dongxu Fu ◽  
Hao Wu ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Artery Occlusion ◽  
Neurological Deficits ◽  
Stroke Model ◽  
Ki 67 ◽  
Ischemic Brain ◽  
Caspase 1 ◽  
And Function ◽  
Cerebral Artery Occlusion ◽  
First Time

Abstract Background Dl-3-n-butylphthalide (NBP) has been widely used for the treatment of ischemic stroke in China. However, its mechanisms of action have not been fully elucidated. Methods We established a permanent middle cerebral artery occlusion (pMCAO) rat model and administered 4 mg/kg/d NBP by tail vein injection for 9 days. Changes in some molecules related to neuroinflammation, neovascularization and nerve regeneration were observed, such as MALDI-TOF MSI to study the distribution of phospholipids in the brain, LA-ICP MSI to observe the changes of Foxp3, Ki-67 and pCREB, immunohistochemistry to investigate NLRP3 and its downstream inflammatory products Caspase-1 and IL-1β. Results These results showed that NBP attenuated ischemic damage in pMCAO rats, accompanied by improving neurological deficits. It was revealed for the first time in an animal stroke model that NBP decreased the levels of PE (18:0), NLRP3, Caspase-1 and IL-1β, while increasing the levels of several phospholipids, such as PA (16:0/18:1), PA (18:0/22:6), PE (16:0/22:6), PE (P-18:0/22:6), PE (18:0/22:6), PS (18:0/22:6), PI (18:0/20:4), Foxp3, Ki-67 and pCREB, in the ischemic brain region. Conclusion These results provide evidence that NBP can reduce neuroinflammation in brain tissue and promote the regeneration of nerves and blood vessels, thus exerting a protective effect on neuromorphology and function.

scholarly journals Delayed inhibition of tonic inhibition enhances functional recovery following experimental ischemic stroke

2017 ◽  
Vol 39 (6) ◽  
pp. 1005-1014 ◽  
Author(s):  
James E Orfila ◽  
Himmat Grewal ◽  
Robert M Dietz ◽  
Frank Strnad ◽  
Takeru Shimizu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Ex Vivo ◽  
Long Term Potentiation ◽  
Artery Occlusion ◽  
Memory Impairments ◽  
Time Points ◽  
Term Potentiation ◽  
Cerebral Artery Occlusion

The current study focuses on the ability to improve cognitive function after stroke with interventions administered at delayed/chronic time points. In light of recent studies demonstrating delayed GABA antagonists improve motor function, we utilized electrophysiology, biochemistry and neurobehavioral methods to investigate the role of α5 GABAA receptors on hippocampal plasticity and functional recovery following ischemic stroke. Male C57Bl/6 mice were exposed to 45 min transient middle cerebral artery occlusion and analysis of synaptic and functional deficits performed 7 or 30 days after recovery. Our findings indicate that hippocampal long-term potentiation (LTP) is impaired 7 days after stroke and remain impaired for at least 30 days. We demonstrate that ex vivo administration of L655,708 reversed ischemia-induced plasticity deficits and importantly, in vivo administration at delayed time-points reversed stroke-induced memory deficits. Western blot analysis of hippocampal tissue reveals proteins responsible for GABA synthesis are upregulated (GAD65/67 and MAOB), increasing GABA in hippocampal interneurons 30 days after stroke. Thus, our data indicate that both synaptic plasticity and memory impairments observed after stroke are caused by excessive tonic GABA activity, making inhibition of specific GABA activity at delayed timepoints a potential therapeutic approach to improve functional recovery and reverse cognitive impairments after stroke.

scholarly journals Treatment Effects of Ischemic Stroke by Berberine, Baicalin, and Jasminoidin from Huang-Lian-Jie-Du-Decoction (HLJDD) Explored by an Integrated Metabolomics Approach

2017 ◽  
Vol 2017 ◽  
pp. 1-20 ◽  
Author(s):  
Qian Zhang ◽  
Xiaowei Fu ◽  
Junsong Wang ◽  
Minghua Yang ◽  
Lingyi Kong
Keyword(s):  
Ischemic Stroke ◽  
Treatment Effects ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
H Nmr ◽  
Abnormal Metabolism ◽  
Cerebral Artery Occlusion ◽  
First Time ◽  
Integrated Metabolomics

Berberine, baicalin, and jasminoidin were major active ingredients of Huang-Lian-Jie-Du-Decoction (HLJDD), a famous prescription of traditional Chinese medicine (TCM), which has been used for the treatment of ischemic stroke. The aim of the present study was to classify their roles in the treatment effects of ischemic stroke. A rat model of middle cerebral artery occlusion (MCAO) was constructed to mimic ischemic stroke and treatment effects of berberine, baicalin, and jasminoidin, and HLJDD was assessed by neurologic deficit scoring, infarct volume, histopathology, immunohistochemistry, biochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. In addition, the 1H NMR metabolomics approach was used to assess the metabolic profiles, which combined with correlation network analysis successfully revealed metabolic disorders in ischemic stroke concerning the treatment of the three principal compounds from HLJDD for the first time. The combined results suggested that berberine, baicalin, and jasminoidin are responsible for the effectiveness of HLJDD on the treatment of ischemic stroke by amelioration of abnormal metabolism and regulation of oxidative stress, neuron autophagy, and inflammatory response. This integrated metabolomics approach showed its potential in understanding the function of complex formulae and clarifying the role of its components in the overall treatment effects.

scholarly journals Depleting SOX2 improves ischemic stroke via lncRNA PVT1/microRNA-24-3p/STAT3 axis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Zhongjun Chen ◽  
Tieping Fan ◽  
Xusheng Zhao ◽  
Zhichen Zhang
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Brain Injury ◽  
Water Content ◽  
Artery Occlusion ◽  
Neurological Deficits ◽  
Neuron Survival ◽  
Non Coding Rna ◽  
Cerebral Artery Occlusion ◽  
And Oxidative Stress

Abstract Objectives Studies have widely explored in the filed of ischemic stroke (IS) with their focus on transcription factors. However, few studies have pivoted on sex determining region Y-box 2 (SOX2) in IS. Thus, this study is launched to figure out the mechanisms of SOX2 in IS. Methods Rat middle cerebral artery occlusion (MCAO) was established as a stroke model. MCAO rats were injected with depleted SOX2 or long non-coding RNA plasmacytoma variant translocation 1 (PVT1) to explore their roles in neurological deficits, cerebral water content, neuron survival, apoptosis and oxidative stress. The relationship among SOX2, PVT1, microRNA (miR)-24-3p and signal transducer and activator of transcription 3 (STAT3) was verified by a series of experiments. Results SOX2, PVT1 and STAT3 were highly expressed while miR-24-3p was poorly expressed in cerebral cortex tissues of MCAO rats. Depleted SOX2 or PVT1 alleviated brain injury in MCAO rats as reflected by neuronal apoptosis and oxidative stress restriction, brain water content reduction, and neurological deficit and neuron survival improvements. Overexpression of PVT1 functioned oppositely. Restored miR-24-3p abolished PVT1 overexpression-induced brain injury in MCAO rats. SOX2 directly promoted PVT1 expression and further increased STAT3 by sponging miR-24-3p. Conclusion This study presents that depleting SOX2 improves IS via PVT1/miR-24-3p/STAT3 axis which may broaden our knowledge about the mechanisms of SOX2/PVT1/miR-24-3p/STAT3 axis and provide a reference of therapy for IS.

scholarly journals A Novel Na + -K + -Cl − Cotransporter 1 Inhibitor STS66* Reduces Brain Damage in Mice After Ischemic Stroke

Stroke ◽  
2019 ◽  
Vol 50 (4) ◽  
pp. 1021-1025 ◽  
Author(s):  
Huachen Huang ◽  
Mohammad Iqbal H. Bhuiyan ◽  
Tong Jiang ◽  
Shanshan Song ◽  
Sandhya Shankar ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Large Vessel ◽  
Neurological Deficits ◽  
Ang Ii ◽  
Cerebral Artery Occlusion

Background and Purpose— Inhibition of brain NKCC1 (Na + -K + -Cl − cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury. Methods— Large-vessel transient ischemic stroke in normotensive C57BL/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)–induced hypertensive C57BL/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66. Results— Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by ≈40% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II–induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion. Conclusions— The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.

scholarly journals Restoration of Polyamine Metabolic Patterns inIn VivoandIn VitroModel of Ischemic Stroke following Human Mesenchymal Stem Cell Treatment

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Tae Hwan Shin ◽  
Geetika Phukan ◽  
Jeom Soon Shim ◽  
Duc-Toan Nguyen ◽  
Yongman Kim ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cell Model ◽  
Glucose Deprivation ◽  
Human Mesenchymal Stem Cell ◽  
Artery Occlusion ◽  
Control Group ◽  
Stem Cell Treatment ◽  
Cerebral Artery Occlusion

We investigated changes in PA levels by the treatment of human bone-marrow-derived mesenchymal stem cells (hBM-MSCs) in ischemic stroke in rat brain model and in cultured neuronal SH-SY5Y cells exposed to oxygen-glucose deprivation (OGD). In ischemic rat model, transient middle cerebral artery occlusion (MCAo) was performed for 2 h, followed by intravenous transplantation of hBM-MSCs or phosphate-buffered saline (PBS) the day following MCAo. Metabolic profiling analysis of PAs was examined in brains from three groups: control rats, PBS-treated MCAo rats (MCAo), and hBM-MSCs-treated MCAo rats (MCAo + hBM-MSCs). In ischemic cell model, SH-SY5Y cells were exposed to OGD for 24 h, treated with hBM-MSCs (OGD + hBM-MSCs) prior to continued aerobic incubation, and then samples were collected after coculture for 72 h. In thein vivoMCAo ischemic model, levels of some PAs in brain samples of the MCAo and MCAo + hBM-MSCs groups were significantly different from those of the control group. In particular, putrescine, cadaverine, and spermidine in brain tissues of the MCAo + hBM-MSCs group were significantly reduced in comparison to those in the MCAo group. In thein vitroOGD system,N1-acetylspermidine, spermidine,N1-acetylspermine, and spermine in cells of the OGD + hBM-MSCs group were significantly reduced compared to those of OGD group.

scholarly journals Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats

2015 ◽  
Vol 36 (8) ◽  
pp. 1374-1383 ◽  
Author(s):  
Da Zhi Liu ◽  
Glen C Jickling ◽  
Bradley P Ander ◽  
Heather Hull ◽  
Xinhua Zhan ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Whole Blood ◽  
Target Genes ◽  
Brain Infarction ◽  
Artery Occlusion ◽  
Neurological Deficits ◽  
Stroke Outcomes ◽  
Vessel Integrity ◽  
Cerebral Artery Occlusion

Because our recent studies have demonstrated that miR-122 decreased in whole blood of patients and in whole blood of rats following ischemic stroke, we tested whether elevating blood miR-122 would improve stroke outcomes in rats. Young adult rats were subjected to a temporary middle cerebral artery occlusion (MCAO) or sham operation. A polyethylene glycol-liposome-based transfection system was used to administer a miR-122 mimic after MCAO. Neurological deficits, brain infarction, brain vessel integrity, adhesion molecule expression and expression of miR-122 target and indirect-target genes were examined in blood at 24 h after MCAO with or without miR-122 treatment. miR-122 decreased in blood after MCAO, whereas miR-122 mimic elevated miR-122 in blood 24 h after MCAO. Intravenous but not intracerebroventricular injection of miR-122 mimic decreased neurological deficits and brain infarction, attenuated ICAM-1 expression, and maintained vessel integrity after MCAO. The miR-122 mimic also down-regulated direct target genes (e.g. Vcam1, Nos2, Pla2g2a) and indirect target genes (e.g. Alox5, Itga2b, Timp3, Il1b, Il2, Mmp8) in blood after MCAO which are predicted to affect cell adhesion, diapedesis, leukocyte extravasation, eicosanoid and atherosclerosis signaling. The data show that elevating miR-122 improves stroke outcomes and we postulate this occurs via downregulating miR-122 target genes in blood leukocytes.

scholarly journals Involvement of the Microglial Aryl Hydrocarbon Receptor in Neuroinflammation and Vasogenic Edema after Ischemic Stroke

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 718
Author(s):  
Miki Tanaka ◽  
Masaho Fujikawa ◽  
Ami Oguro ◽  
Kouichi Itoh ◽  
Christoph F. A. Vogel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemic Stroke ◽  
Aryl Hydrocarbon Receptor ◽  
Vasogenic Edema ◽  
Artery Occlusion ◽  
Aryl Hydrocarbon ◽  
Inflammatory Conditions ◽  
Severity Scores ◽  
Factor Α ◽  
Cerebral Artery Occlusion

Microglia are activated after ischemic stroke and induce neuroinflammation. The expression of the aryl hydrocarbon receptor (AhR) has recently been reported to elicit cytokine expression. We previously reported that microglial activation mediates ischemic edema progression. Thus, the purpose of this study was to examine the role of AhR in inflammation and edema after ischemia using a mouse middle cerebral artery occlusion (MCAO) model. MCAO upregulated AhR expression in microglia during ischemia. MCAO increased the expression of tumor necrosis factor α (TNFα) and then induced edema progression, and worsened the modified neurological severity scores, with these being suppressed by administration of an AhR antagonist, CH223191. In THP-1 macrophages, the NADPH oxidase (NOX) subunit p47phox was significantly increased by AhR ligands, especially under inflammatory conditions. Suppression of NOX activity by apocynin or elimination of superoxide by superoxide dismutase decreased TNFα expression, which was induced by the AhR ligand. AhR ligands also elicited p47phox expression in mouse primary microglia. Thus, p47phox may be important in oxidative stress and subsequent inflammation. In MCAO model mice, P47phox expression was upregulated in microglia by ischemia. Lipid peroxidation induced by MCAO was suppressed by CH223191. Taken together, these findings suggest that AhR in the microglia is involved in neuroinflammation and subsequent edema, after MCAO via p47phox expression upregulation and oxidative stress.

scholarly journals Synthesis of Paeonol-Ozagrel Conjugate: Structure Characterization and In Vivo Anti-Ischemic Stroke potential

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing Zhang ◽  
Miaomiao Jiang ◽  
Hui Zhao ◽  
Lan Han ◽  
Yu Jin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Artery Occlusion ◽  
Structure Characterization ◽  
Drug Candidate ◽  
Resonance Spectroscopy ◽  
Cerebral Artery Occlusion

Ischemic stroke is a common neurological disease that can lead to mortality and disability. The current curative effect remains unsatisfactory because drug accumulation in the diseased areas is insufficient as a result of the unique blood–brain barrier. Therefore, much attention has been paid to develop a novel therapeutic compound, paeonol-ozagrel conjugate (POC), for ischemic stroke. Then, POC was successfully synthesized by conjugating of paeonol and ozagrel as mutual prodrug. A series of in vitro characterizations and evaluations, including high - resolution mass spectroscopy, nuclear magnetic resonance spectroscopy, partition coefficient, and assessment of cytotoxicity against PC12 cells, were performed. Pharmacokinetic study demonstrated POC is eliminated quickly (t1/2 = 53.46 ± 19.64 min), which supported a short dosing interval. The neurological score, infarct volume, histopathological changes, oxidative stress, inflammatory cytokines levels, and TXA2 levels also were evaluated in vivo in middle cerebral artery occlusion (MCAO) rats. All results showed that POC had a significant curative and therapeutic effect on ischemic stroke, as evaluated by the middle cerebral artery occlusion. Overall, POC can be expected to become a new drug candidate for the treatment of ischemic stroke.

scholarly journals A review of experimental models of focal cerebral ischemia focusing on the middle cerebral artery occlusion model

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 242
Author(s):  
Melissa Trotman-Lucas ◽  
Claire L. Gibson
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Artery Occlusion ◽  
Lesion Volume ◽  
Mechanistic Investigation ◽  
Cerebral Artery Occlusion

Cerebral ischemic stroke is a leading cause of death and disability, but current pharmacological therapies are limited in their utility and effectiveness. In vitro and in vivo models of ischemic stroke have been developed which allow us to further elucidate the pathophysiological mechanisms of injury and investigate potential drug targets. In vitro models permit mechanistic investigation of the biochemical and molecular mechanisms of injury but are reductionist and do not mimic the complexity of clinical stroke. In vivo models of ischemic stroke directly replicate the reduction in blood flow and the resulting impact on nervous tissue. The most frequently used in vivo model of ischemic stroke is the intraluminal suture middle cerebral artery occlusion (iMCAO) model, which has been fundamental in revealing various aspects of stroke pathology. However, the iMCAO model produces lesion volumes with large standard deviations even though rigid surgical and data collection protocols are followed. There is a need to refine the MCAO model to reduce variability in the standard outcome measure of lesion volume. The typical approach to produce vessel occlusion is to induce an obstruction at the origin of the middle cerebral artery and reperfusion is reliant on the Circle of Willis (CoW). However, in rodents the CoW is anatomically highly variable which could account for variations in lesion volume. Thus, we developed a refined approach whereby reliance on the CoW for reperfusion was removed. This approach improved reperfusion to the ischemic hemisphere, reduced variability in lesion volume by 30%, and reduced group sizes required to determine an effective treatment response by almost 40%. This refinement involves a methodological adaptation of the original surgical approach which we have shared with the scientific community via publication of a visualised methods article and providing hands-on training to other experimental stroke researchers.

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