scholarly journals Screening Potential Therapeutic Mechanisms of Houshiheisan Against Ischemic Stroke by LncRNAs and MRNAs Microarray Profiling

2021 ◽  
Author(s):  
Hong-Fa Cheng ◽  
Ya-Wen Zhang ◽  
Xiao-Yao Guo ◽  
Han-Yu Wang ◽  
Xuan Wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Artery Occlusion ◽  
Differentially Expressed ◽  
Dynamic Interactions ◽  
Pathway Network ◽  
Detection Analysis ◽  
Microarray Expression ◽  
Cerebral Artery Occlusion

Abstract Background Long non-coding RNAs (lncRNAs) are substantial to wide varity of biological processes and pathogenesis processes of ischemic stroke. Houshiheisan (HSHS), a typical prescription of traditional Chinese medicine, has outstanding efficacy in treating stroke, although the comprehensive molecular mechanism of its therapeutic effect has remained obscure up to now. Methods In this work, we induced a ischemic stroke rat model by permanent middle cerebral artery occlusion (MCAO). The microarray expression profile of lncRNAs and mRNAs was used to investigate various possible roles and molecular mechanism of HSHS in treating MCAO rats. Results HSHS improved the neurological deficit and alleviated the pathological damage after cerebral ischemia. The Clariom D Assay (rat, Affymetrix) showed that 8128 mRNAs and 3022 lncRNAs differentially expressed between sham group and model group, and 868 mRNAs and 836 lncRNAs between HSHS and model groups. Among the three groups, the intersections (666 mRNAs and 288 lncRNAs) were chosen and analyzed. GO and KEGG analysis disclosed that the majority of overlapping mRNAs were enriched in Axon guidance, Autophagy, PI3K-AKT signaling pathway and mTOR signaling pathway. Pathway network, protein-protein network and molecular complex detection analysis identified significant hub genes, e.g., Rock2, Rps6kb1, Wnt4, IL-6 and so on. Furthermore, we explored dynamic interactions between the dysregulated lncRNAs and mRNAs by lncRNA-mRNA network analysis. Finally, qRT-PCR verified expressions of the critical differentially expressed lncRNAs and mRNAs within the three groups. Conclusion Our results indicate that these differentially expressed lncRNAs may affect pathological processes of ischemic stroke by regulating co-expressed mRNAs, providing novel insight in regarding lncRNAs’ involvement in the treatment of ischemic stroke.

scholarly journals Neuroprotective Effect of SCM-198 through Stabilizing Endothelial Cell Function

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Qiu-Yan Zhang ◽  
Zhi-Jun Wang ◽  
Lei Miao ◽  
Ying Wang ◽  
Ling-Ling Chang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Cell Function ◽  
Neuroprotective Effect ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Oxygen Glucose Deprivation ◽  
Endothelial Cell Function ◽  
Cerebral Artery Occlusion

Leonurine, also named SCM-198, which was extracted from Herba leonuri, displayed a protective effect on various cardiovascular and brain diseases, like ischemic stroke. Ischemic stroke which is the leading cause of morbidity and mortality, ultimately caused irreversible neuron damage. This study is aimed at exploring the possible therapeutic potential of SCM-198 in the protection against postischemic neuronal injury and possible underlying mechanisms. A transient middle cerebral artery occlusion (tMCAO) rat model was utilized to measure the protective effect of SCM-198 on neurons. TEM was used to determine neuron ultrastructural changes. The brain slices were stained with Nissl staining solution for Nissl bodies. Fluoro-Jade B (FJB) was used for staining the degenerating neurons. In the oxygen-glucose deprivation and re-oxygenation (OGD/R) model of bEnd.3 cells treated with SCM-198 (0.1, 1, 10 μM). Then, the bEnd.3 cells were cocultured with SH-SY5Y cells. Cell viability, MDA level, CAT activity, and apoptosis were examined to evaluate the cytotoxicity of these treatments. Western blot and immunofluorescent assays were used to examine the expression of protein related to the p-STAT3/NOX4/Bcl-2 signaling pathway. Coimmunoprecipitation was performed to determine the interaction between p-STAT3 and NOX4. In the transient middle cerebral artery occlusion (tMCAO) rat model, we found that treatment with SCM-198 could ameliorate neuron morphology and reduce the degenerating cell and neuron loss. In the in vitro model of bEnd.3 cell oxygen-glucose deprivation and reoxygenation (OGD/R), treatment with SCM-198 restored the activity of catalase (CAT), improved the expression of Cu-Zn superoxide dismutase (SOD1), and decreased the malondialdehyde (MDA) production. SCM-198 treatment prevented OGD/R-induced cell apoptosis as indicated by increased cell viability and decreased the number of TUNEL-positive cells, accompanied with upregulation of Bcl-2 and Bcl-xl protein and downregulation Bax protein. The results were consistent with SH-SY5Y cells which coculture with bEnd.3 cells. The forthcoming study revealed that SCM-198 activated the p-STAT3/NOX4/Bcl-2 signaling pathway. All the data indicated that SCM-198 protected against oxidative stress and neuronal damage in in vivo and in vitro injury models via the p-STAT3/NOX4/Bcl-2 signaling pathway. Our results suggested that SCM-198 could be the potential drug for neuroprotective effect through stabilizing endothelial cell function.

Energy-Sensing Pathways in Ischemia: The Counterbalance Between AMPK and mTORC

2020 ◽  
Vol 25 (45) ◽  
pp. 4763-4770
Author(s):  
Angel Cespedes ◽  
Mario Villa ◽  
Irene Benito-Cuesta ◽  
Maria J. Perez-Alvarez ◽  
Lara Ordoñez ◽  
...  
Keyword(s):  
Blood Flow ◽  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Cause Of Death ◽  
Artery Occlusion ◽  
Brain Pathology ◽  
Common Cause ◽  
Specific Analysis ◽  
Energy Sensing ◽  
Cerebral Artery Occlusion

: Stroke is an important cause of death and disability, and it is the second leading cause of death worldwide. In humans, middle cerebral artery occlusion (MCAO) is the most common cause of ischemic stroke. The damage occurs due to the lack of nutrients and oxygen contributed by the blood flow. : The present review aims to analyze to what extent the lack of each of the elements of the system leads to damage and which mechanisms are unaffected by this deficiency. We believe that the specific analysis of the effect of lack of each component could lead to the emergence of new therapeutic targets for this important brain pathology.

Cerebrolysin and Aquaporin 4 Inhibition Improve Pathological and Motor Recovery after Ischemic Stroke

2018 ◽  
Vol 17 (4) ◽  
pp. 299-308 ◽  
Author(s):  
Bogdan Catalin ◽  
Otilia-Constantina Rogoveanu ◽  
Ionica Pirici ◽  
Tudor Adrian Balseanu ◽  
Adina Stan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Vasogenic Edema ◽  
Artery Occlusion ◽  
Aquaporin 4 ◽  
Hypertonic Solution ◽  
Water Metabolism ◽  
Scar Region ◽  
Function Preservation ◽  
Neurotropic Factor ◽  
Cerebral Artery Occlusion

Background: Edema represents one of the earliest negative markers of survival and consecutive neurological deficit following stroke. The mixture of cellular and vasogenic edema makes treating this condition complicated, and to date, there is no pathogenically oriented drug treatment for edema, which leaves parenteral administration of a hypertonic solution as the only non-surgical alternative. Objective: New insights into water metabolism in the brain have opened the way for molecular targeted treatment, with aquaporin 4 channels (AQP4) taking center stage. We aimed here to assess the effect of inhibiting AQP4 together with the administration of a neurotropic factor (Cerebrolysin) in ischemic stroke. Methods: Using a permanent medial cerebral artery occlusion rat model, we administrated a single dose of the AQP4 inhibitor TGN-020 (100 mg/kg) at 15 minutes after ischemia followed by daily Cerebrolysin dosing (5ml/kg) for seven days. Rotarod motor testing and neuropathology examinations were next performed. Results: We showed first that the combination treatment animals have a better motor function preservation at seven days after permanent ischemia. We have also identified distinct cellular contributions that represent the bases of behavior testing, such as less astrocyte scarring and a larger neuronalsurvival phenotype rate in animals treated with both compounds than in animals treated with Cerebrolysin alone or untreated animals. Conclusion: Our data show that water diffusion inhibition and Cerebrolysin administration after focal ischemic stroke reduces infarct size, leading to a higher neuronal survival in the peri-core glial scar region.

scholarly journals The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke

2021 ◽  
Author(s):  
Yong-Ming Zhu ◽  
Liang Lin ◽  
Chao Wei ◽  
Yi Guo ◽  
Yuan Qin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Glial Scar ◽  
Scar Formation ◽  
Reactive Astrocytes ◽  
Interacting Protein ◽  
Protein Levels ◽  
Endothelial Growth Factor ◽  
Cerebral Artery Occlusion

AbstractNecroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown. Here, in a transient middle cerebral artery occlusion (tMCAO) rat model and an oxygen and glucose deprivation and reoxygenation (OGD/Re)-induced astrocytic injury model, we show that RIP1K was significantly elevated in the reactive astrocytes. Knockdown of RIP1K or delayed administration of RIP1K inhibitor Nec-1 down-regulated the glial scar markers, improved ischemic stroke-induced necrotic morphology and neurologic deficits, and reduced the volume of brain atrophy. Moreover, knockdown of RIP1K attenuated astrocytic cell death and proliferation and promoted neuronal axonal generation in a neuron and astrocyte co-culture system. Both vascular endothelial growth factor D (VEGF-D) and its receptor VEGFR-3 were elevated in the reactive astrocytes; simultaneously, VEGF-D was increased in the medium of astrocytes exposed to OGD/Re. Knockdown of RIP1K down-regulated VEGF-D gene and protein levels in the reactive astrocytes. Treatment with 400 ng/ml recombinant VEGF-D induced the formation of glial scar; conversely, the inhibitor of VEGFR-3 suppressed OGD/Re-induced glial scar formation. RIP3K and MLKL may be involved in glial scar formation. Taken together, these results suggest that RIP1K participates in the formation of astrogliosis and glial scar via impairment of normal astrocyte responses and enhancing the astrocytic VEGF-D/VEGFR-3 signaling pathways. Inhibition of RIP1K promotes the brain functional recovery partially via suppressing the formation of astrogliosis and glial scar. Graphical Abstract

Abstract 166: Endothelial Overexpression of LOX-1 Increases Stroke Size in vivo

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Alexander Akhmedov ◽  
Remo D Spescha ◽  
Francesco Paneni ◽  
Giovani G Camici ◽  
Thomas F Luescher
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Endothelial Dysfunction ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Oxidized Ldl ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion ◽  
The Brain

Background— Stroke is one of the most common causes of death and long term disability worldwide primarily affecting the elderly population. Lectin-like oxidized LDL receptor 1 (LOX-1) is the receptor for oxidized LDL identified in endothelial cells. Binding of OxLDL to LOX-1 induces several cellular events in endothelial cells, such as activation of transcription factor NF-kB, upregulation of MCP-1, and reduction in intracellular NO. Accumulating evidence suggests that LOX-1 is involved in endothelial dysfunction, inflammation, atherogenesis, myocardial infarction, and intimal thickening after balloon catheter injury. Interestingly, a recent study demonstrated that acetylsalicylic acid (aspirin), which could prevent ischemic stroke, inhibited Ox-LDL-mediated LOX-1 expression in human coronary endothelial cells. The expression of LOX-1 was increased at a transient ischemic core site in the rat middle cerebral artery occlusion model. These data suggest that LOX-1 expression induces atherosclerosis in the brain and is the precipitating cause of ischemic stroke. Therefore, the goal of the present study was to investigate the role of endothelial LOX-1 in stroke using experimental mouse model. Methods and Results— 12-week-old male LOX-1TG generated recently in our group and wild-type (WT) mice were applied for a transient middle cerebral artery occlusion (MCAO) model to induce ischemia/reperfusion (I/R) brain injury. LOX-1TG mice developed 24h post-MCAO significantly larger infarcts in the brain compared to WT (81.51±8.84 vs. 46.41±10.13, n=7, p < 0.05) as assessed morphologically using Triphenyltetrazolium chloride (TTC) staining. Moreover, LOX-1TG showed higher neurological deficit in RotaRod (35.57±8.92 vs. 66.14±10.63, n=7, p < 0.05) and Bederson tests (2.22±0.14 vs. 1.25±0.30, n=9-12, p < 0.05) - two experimental physiological tests for neurological function. Conclusions— Thus, our data suggest that LOX-1 plays a critical role in the ischemic stroke when expressed at unphysiological levels. Such LOX-1 -associated phenotype could be due to the endothelial dysfunction. Therefore, LOX-1 may represent novel therapeutic targets for preventing ischemic stroke.

scholarly journals A Novel Model for Encephalomyosynangiosis Surgery after Middle Cerebral Artery Occlusion-Induced Stroke in Mice

2021 ◽  
Author(s):  
Mitch Paro ◽  
Daylin Gamiotea Turro ◽  
Leslie Blumenfeld ◽  
Ketan R Bulsara ◽  
Rajkumar Verma
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Artery Occlusion ◽  
Novel Treatment ◽  
Graft Tissue ◽  
Cerebral Artery Occlusion

Background and Purpose: No effective treatment is available for most patients who suffer ischemic stroke. Development of novel treatment options is imperative. The brain attempts to self-heal after ischemic stroke via various mechanism mediated by restored blood circulation in affected region of brain but this process is limited by inadequate angiogenesis or neoangiogenesis. Encephalomyosynangiosis (EMS) is a neurosurgical procedure that achieves angiogenesis with low morbidity in patients with moyamoya disease, reducing risk of stroke. However, EMS, surgery has never been studied as an therapeutic option after ischemic stroke. Here we described a novel procedure and feasibility data for EMS after ischemic stroke in mice. Methods: A 60 mins of middle cerebral artery occlusion (MCAo) was used to induce ischemic stroke in mice. After 3-4 hours of MCAo onset/sham, EMS was performed. Mortality of EMS, MCAo and. MCAo+EMS mice was recorded up to 21 days after surgery. Graft tissue viability was measured using a nicotinamide adenine dinucleotide reduced tetrazolium reductase assay. Results: EMS surgery after ischemic stroke does not increase mortality compared to stroke alone. Graft muscle tissue remained viable 21 days after surgery. Conclusions: This novel protocol is effective and well-tolerated, may serve as novel platform for new angiogenesis and thus recovery after ischemic stroke. If successful in mice, EMS can a very feasible and novel treatment option for ischemic stroke in humans.

Abstract 1029: Stromelysin-1 is Critical For Intracranial Bleeding After Tissue-type plasminogen activator Treatment Of Stroke In Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yasuhiro Suzuki ◽  
Nobuo Nagai ◽  
Desire Collen ◽  
Roger Lijnen ◽  
Kazuo Umemura
Keyword(s):  
Ischemic Stroke ◽  
Plasminogen Activator ◽  
Placebo Treatment ◽  
Artery Occlusion ◽  
Intracranial Bleeding ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Mmp Inhibitor ◽  
Type Plasminogen Activator ◽  
Cerebral Artery Occlusion

Background: Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it may increase the risk of intracranial bleeding (ICB). Matrix metalloproteinases (MMPs), which can be activated through the plasminogen/plasmin system, may contribute to ICB after ischemic stroke. Objectives: To explore the contribution of plasminogen, MMP-3 and MMP-9 to ICB associated with t-PA treatment after ischemic stroke. Methods: Using a thrombotic middle cerebral artery occlusion (MCA-O) model, ICB was studied in mice with genetic deficiencies of plasminogen (Plg −/ − ), stromelysin-1 (MMP-3 −/ − ) or gelatinase B (MMP-9 −/ − ) and their corresponding wild-type (WT) littermates. t-PA (10 mg/kg) or its equivalent volume of solvent was administered intravenously 4 hours after MCA-O. The induction of MMP-3 and MMP-9 was also studied in C57BL/6 WT mice. Results: In MMP-3 +/+ WT mice given solvent, ICB was 4.3 ± 2.9 mm 3 (mean ± SD), which was significantly increased with tPA treatment to 9.7 ± 4.7 mm 3 (P<0.05), whereas ICB in MMP-3 −/ − mice was not altered by t-PA treatment (5.7 ± 2.7 mm 3 , as compared to 5.1 ± 1.8 mm 3 without tPA; n = 7–9 in each group). ICB induced by t-PA was significantly less in Plg −/ − (5.7 ± 3.9 mm 3 ) than in WT mice (8.8 ± 3.2 mm 3 , p<0.05) but ICB by t-PA in MMP-9 −/ − (8.3 ± 2.3 mm 3 ) was comparable with that in WT (8.3 ± 3.1 mm 3 ; n=8 –12 in each group). Administration of the broad-spectrum MMP inhibitor GM6001 after t-PA treatment reduced ICB significantly in MMP-3 +/+ (from 6.4 ± 1.9 mm 3 to 4.1 ± 1.9 mm 3 , p<0.05) but not in MMP-3 −/ − mice (2.2 ± 0.6 mm 3 without versus 2.9 ± 1.5 mm 3 with GM6001; n=6 – 8 in each group). MMP-3 expression was significantly enhanced at the ischemic hemisphere; with placebo treatment, it was expressed only in neurons, whereas it was upregulated in endothelial cells with t-PA treatment. Although MMP-9 expression was also significantly enhanced at the ischemic brain, the amount and the distribution were comparable in mice with and without t-PA treatment. Conclusions: Our data with gene deficient mice suggest that plasminogen and MMP-3 are relatively more important than MMP-9 for the increased ICB induced by t-PA treatment of ischemic stroke.

Blocking A1 astrocyte conversion with semaglutide attenuates blood-brain barrier disruption in mice after middle cerebral artery occlusion

2021 ◽  
Author(s):  
Qi Zhang ◽  
Chang Liu ◽  
Rubing Shi ◽  
Huimin Shan ◽  
Lidong Deng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Middle Cerebral Artery ◽  
Signaling Pathways ◽  
Middle Cerebral Artery Occlusion ◽  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Rna Seq ◽  
Neurobehavioral Outcomes ◽  
Cerebral Artery Occlusion

Abstract Background Astrocytes play an essential role in the modulation of blood-brain barrier function. Neurological diseases induce astrocytes to transform into a neurotoxic A1 phenotype, thus exacerbating brain injury. However, the effect of A1 astrocyte on the function of BBB after stroke is unknown. Method: Adult male ICR mice (n = 78) were subjected to 90-minute transient middle cerebral artery occlusion. Immunohistochemical staining of A1 (C3d) and A2 (S100A10) was performed to characterize phenotypic changes of astrocytes overtime after stroke. Glucagon-like peptide-1 receptor agonist semaglutide was intraperitoneally injected into the mice to inhibit A1 astrocyte. Infarct volume, atrophy volume, neurobehavioral outcomes, and BBB permeability were examined. RNA-seq was adopted to explore the potential targets and signaling pathways of A1 astrocytes induced BBB dysfunction. Results Astrocytes assumed the A2 phenotype at the early stage of ischemic stroke but gradually transformed to the A1 phenotype. Semaglutide treatment reduced M1 microglia polarization and A1 astrocytes conversion after ischemic stroke (p < 0.05). Ischemia induced brain infarct volume, atrophy volume and neuroinflammation were reduced in the semaglutide treated mice. Neurobehavioral outcomes were improved compared to the control mice (p < 0.05). Further study demonstrated that semaglutide treatment reduced the gap formation of tight junction proteins ZO-1, claudin-5 and occludin, as well as IgG leakage following three days of ischemic stroke (p < 0.05). In vitro experiments revealed that A1 astrocyte-conditioned medium disrupted BBB integrity. RNA-seq further showed that A1 astrocytes were enriched in inflammatory factors and chemokines, as well as significantly modulating TNF and chemokine signaling pathways, which are closely related to barrier damage. Conclusion We concluded that astrocytes undergo a conversion from A2 phenotype to A1 phenotype overtime after ischemic stroke. A1 astrocytes aggravated BBB disruption, suggesting that block of A1 astrocytes conversion provides a novel strategy for the treatment of ischemic stroke.

Sign in / Sign up

Export Citation Format

Share Document