scholarly journals 8e Protects against Acute Cerebral Ischemia by Inhibition of PI3Kγ-Mediated Superoxide Generation in Microglia

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2828 ◽  
Author(s):  
Linna Wang ◽  
Xiaoli Wang ◽  
Tingting Li ◽  
Yihua Zhang ◽  
Hui Ji
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Critical Role ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Potential Candidate ◽  
Promising Target ◽  
Acute Cerebral Ischemia ◽  
Penumbral Region ◽  
Phosphoinositide 3 Kinase

The inflammatory response mediated by microglia plays a critical role in the progression of ischemic stroke. Phosphoinositide 3-kinase gamma (PI3Kγ) has been implicated in multiple inflammatory and autoimmune diseases, making it a promising target for therapeutic intervention. The aim of this study was to evaluate the efficacy of 8e, a hydrogen sulfide (H2S) releasing derivative of 3-n-butylphthalide (NBP), on brain damage and PI3Kγ signaling following cerebral ischemia injury. 8e significantly reduced sensorimotor deficits, focal infarction, brain edema and neural apoptosis at 72 h after transient middle cerebral artery occlusion (tMCAO). The NOX2 isoform of the NADPH oxidase family is considered a major enzymatic source of superoxide. We found that the release of superoxide, together with the expression of NOX2 subunits p47phox, p-p47phox, and the upstream PI3Kγ/AKT signaling were all down-regulated by 8e, both in the penumbral region of the rat brain and in the primary cultured microglia subjected to oxygen-glucose deprivation (OGD). With the use of siRNA and pharmacological inhibitors, we further demonstrated that 8e regulates the formation of superoxide in activated microglia through the PI3Kγ/AKT/NOX2 signaling pathway and subsequently prevents neuronal death in neighboring neurons. Our experimental data indicate that 8e is a potential candidate for the treatment of ischemic stroke and PI3Kγ-mediated neuroinflammation.

scholarly journals Up-regulation of miR-499a-5p decreases cerebral ischemia/reperfusion injury by targeting PDCD4

2021 ◽  
Author(s):  
Weifeng Shan ◽  
Huifeng Ge ◽  
Bingquan Chen ◽  
Linger Huang ◽  
Shaojun Zhu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Cell Model ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Tunel Staining ◽  
Cerebral Ischemia Reperfusion

Abstract MiR-499a-5p was significantly down-regulated in degenerative tissues and correlated with apoptosis. Nonetheless, the biological function of miR-499a-5p in acute ischemic stroke has been still unclear. In this study, we found the plasma levels of miR-499a-5p were significantly down-regulated in 64 ischemic stroke patients and negatively correlated with the National Institutes of Health Stroke Scale score. Then, we constructed cerebral ischemia/reperfusion (I/R) injury in rats after middle cerebral artery occlusion and subsequent reperfusion and oxygen-glucose deprivation and reoxygenation (OGD/R) treated SH-SY5Y cell model. Transfection with miR-499a-5p mimic was accomplished by intracerebroventricular injection in the in vivo I/R injury model. We further found miR-499a-5p overexpression decreased infarct volumes and cell apoptosis in the in vivo I/R stroke model using TTC and TUNEL staining. PDCD4 was a direct target of miR-499a-5p by luciferase report assay and western blotting. Knockdown of PDCD4 reduced the infarct damage and cortical neuron apoptosis caused by I/R injury. MiR-499a-5p exerted neuroprotective roles mainly through inhibiting PDCD4-mediated apoptosis by CCK-8 assay, LDH release assay and flow cytometry analysis. These findings suggest that miR-499a-5p might represent a novel target that regulates brain injury by inhibiting PDCD4-mediating apoptosis.

scholarly journals Gonadal Hormones E2 and P Mitigate Cerebral Ischemia-Induced Upregulation of the AIM2 and NLRC4 Inflammasomes in Rats

2020 ◽  
Vol 21 (13) ◽  
pp. 4795
Author(s):  
Pardes Habib ◽  
Julie Harms ◽  
Adib Zendedel ◽  
Cordian Beyer ◽  
Alexander Slowik
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Single Cell ◽  
Cell Cultures ◽  
Glucose Deprivation ◽  
Gonadal Hormones ◽  
Artery Occlusion ◽  
Protein Levels ◽  
Cortical Astrocytes

Acute ischemic stroke (AIS) is a devastating neurological condition with a lack of neuroprotective therapeutic options, despite the reperfusion modalities thrombolysis and thrombectomy. Post-ischemic brain damage is aggravated by an excessive inflammatory cascade involving the activation and regulation of the pro-inflammatory cytokines IL-1β and IL-18 by inflammasomes. However, the role of AIM2 and NLRC4 inflammasomes and the influence of the neuroprotective steroids 17β-estradiol (E2) and progesterone (P) on their regulation after ischemic stroke have not yet been conclusively elucidated. To address the latter, we subjected a total of 65 rats to 1 h of transient Middle Cerebral Artery occlusion (tMCAO) followed by a reperfusion period of 72 h. Moreover, we evaluated the expression and regulation of AIM2 and NLRC4 in glial single-cell cultures (astroglia and microglia) after oxygen–glucose deprivation (OGD). The administration of E2 and P decreased both infarct sizes and neurological impairments after cerebral ischemia in rats. We detected a time-dependent elevation of gene and protein levels (Western Blot/immunohistochemistry) of the AIM2 and NLRC4 inflammasomes in the post-ischemic brains. E2 or P selectively mitigated the stroke-induced increase of AIM2 and NLRC4. While both inflammasomes seemed to be exclusively abundant in neurons under physiological and ischemic conditions in vivo, single-cell cultures of cortical astrocytes and microglia equally expressed both inflammasomes. In line with the in vivo data, E and P selectively reduced AIM2 and NLRC4 in primary cortical astrocytes and microglial cells after OGD. In conclusion, the post-ischemic elevation of AIM2 and NLRC4 and their down-regulation by E2 and P may shed more light on the anti-inflammatory effects of both gonadal hormones after stroke.

scholarly journals Prunus cerasoides Extract and Its Component Compounds Upregulate Neuronal Neuroglobin Levels, Mediate Antioxidant Effects, and Ameliorate Functional Losses in the Mouse Model of Cerebral Ischemia

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 99
Author(s):  
So-Dam Kim ◽  
Minha Kim ◽  
Hong-Hua Wu ◽  
Byung Kwan Jin ◽  
Myung-Shin Jeon ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Mouse Model ◽  
Infarct Volume ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Novel Approach ◽  
Vehicle Treatment ◽  
Prunus Cerasoides

Prunus cerasoides (PC) has been reported to have antimicrobial and anti-inflammatory properties, but its potential as a neuroprotective agent in a mouse model of cerebral ischemia has not been explored. Considering neuroglobin (Ngb), an endogenous neuroprotective factor, as a novel approach to neuroprotection, in this study, Ngb promoter activity, Ngb expression changes, and antioxidant protection by PC extract (PCE) and PC component compounds (PCCs) were analyzed in oxygen–glucose deprivation (OGD)-treated neurons. In vivo analysis involved transient middle cerebral artery occlusion (tMCAO) in mice with pre- and post-treatment exposure to PCE. Following ischemic stroke induction, neurological behavior scores were obtained, and cellular function-related signals were evaluated in the ischemic infarct areas. In addition to PCE, certain component compounds from PCE also significantly increased Ngb levels and attenuated the intracellular ROS production and cytotoxicity seen with OGD in primary neurons. Administration of PCE reduced the infarct volume and improved neurological deficit scores in ischemic stroke mice compared with the vehicle treatment. Increased Ngb levels in infarct penumbra with PCE treatment were also accompanied by decreased markers of apoptosis (activated p38 and cleaved caspase-3). Our findings point to the benefits of Ngb-mediated neuroprotection via PCE and its antioxidant activity in an ischemic stroke model.

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

scholarly journals LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-κB and JAK2/STAT3

Human Cell ◽  
2021 ◽  
Author(s):  
Jiaying Zhu ◽  
Zhu Zhu ◽  
Yipin Ren ◽  
Yukang Dong ◽  
Yaqi Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Mice Model ◽  
Down Regulation

AbstractLINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen–glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke.

Abstract T P167: Emergent Identification of Type A Aortic Dissection as a Cause of Acute Ischemic Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Tomoyuki Ohara ◽  
Kazunori Toyoda ◽  
Hiroyuki Yokoyama ◽  
Kenji Minatoya ◽  
Eijiro Tanaka ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Back Pain ◽  
Cerebral Ischemia ◽  
Aortic Dissection ◽  
Intravenous Thrombolysis ◽  
Type A ◽  
Neurological Deficits ◽  
Diagnostic Tools ◽  
Acute Cerebral Ischemia ◽  
D Dimer

Background: Acute aortic dissection (AAD) sometimes presents with predominant neurological symptoms of acute cerebral ischemia. Fatal AAD patients after thrombolysis for stroke without noticing AAD were reported. The purpose of this study was to clarify the characteristics of AAD patients with acute cerebral ischemia and develop a score to emergently identify AAD for such patients. Methods: From the database of Stanford type A-AAD patients admitted in our hospital between 2007 and 2012, we selected those presenting with acute focal neurological deficits due to ischemic stroke/TIA. Patients presenting with shock state or cardiopulmonary arrest were excluded. Physiological, radiological, and blood examinations were assessed for AAD identification. Results: Of 187 AAD patients, 19 patients (10%) with focal neurological deficits as an initial presentation were studied. Involvement of one or more main branches of the aortic arch was observed in all of 19 patients. Stroke experts, not cardiovascular experts, were primarily called to ER in 18 patients, and 12 were potential candidates for intravenous thrombolysis. Left hemiparesis (14 patients, 74%) was the most common neurological symptom. Nine patients (47%) complained of chest or back pain. As components of the score, (1) systolic BP differential >20mmHg between upper extremities was present in 11 of 17 patients (65%), (2) mediastinal widening on chest radiography in 13/16 (81%), (3) occlusion or the intimal flap of the proximal common carotid artery on carotid ultrasonography in 14/16 (88%), (4) pericardial effusion on echocardiography in 10/19 (47%), and (5) abnormal elevation of D-dimer levels in all 19 (median 24.8 [range 4.2-406.2] μg/ml). Two components were positive in 4 patients, three in 6, four in 5, and all the five in 4. Conclusions: Only half of AAD patients with stroke/TIA complained of chest or back pain. All the AAD patients with stroke/TIA showed high D-dimer levels and one or more additional abnormal findings in physiological and radiological examinations. Combination of such handy diagnostic tools is helpful to identify AAD without long time delay and to avoid unnecessary thrombolysis for AAD patients.

Zuogui Pill Attenuates Neuroinflammation and Improves Cognitive Function in Cerebral Ischemia Reperfusion-Injured Rats

2021 ◽  
pp. 1-8
Author(s):  
Hong Liu ◽  
Qiaomei Dai ◽  
Jing Yang ◽  
Yuwei Zhang ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cerebral Ischemia ◽  
Cell Viability ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Oxygen And Glucose Deprivation ◽  
Infarct Area ◽  
Zuogui Pill ◽  
Adverse Influence

<b><i>Introduction:</i></b> Cerebral ischemia and reperfusion (CI/R) injury is a devasting cerebrovascular disease, accompanied with ischemia stroke, cerebral infarction. Zuogui Pill (ZGP), as a Chinese traditional medicine, is proved to be effective in many diseases and cancers. Our study aimed to detect the roles of ZGP in CI/R injury. <b><i>Methods:</i></b> Neural stem cells were isolated from rats and induced by oxygen and glucose deprivation and recovery. CCK-8 and flow cytometry were applied to assess the function of ZGP on cell viability and apoptosis. Rat CI/R injury models were established by the middle cerebral artery occlusion and reperfusion. The function of ZGP on CI/R injury was identified via evaluating modified neurological severity score, infarct area, and cognitive impairment. <b><i>Results:</i></b> Compared to the control, the cell viability was obviously decreased in the oxygen and glucose deprivation and recovery (OGD/R) group, while the adverse influence on cells was reversed by cultured plus 10% ZGP serum. Consistently, ZGP attenuated the influence of OGD/R on cell apoptosis. More importantly, ZGP could alleviate CI/R injury of rats by reducing neurological damage and infarct area and promoting cognitive function. <b><i>Conclusion:</i></b> This study provided protective roles of ZGP on cell viability and apoptosis induced by OGD/R. In addition, ZGP played protective roles on neuroinflammation and cognitive function in rats.

scholarly journals The Rapid Decrease in Astrocyte-Associated Dystroglycan Expression by Focal Cerebral Ischemia is Protease-Dependent

2007 ◽  
Vol 28 (4) ◽  
pp. 812-823 ◽  
Author(s):  
Richard Milner ◽  
Stephanie Hung ◽  
Xiaoyun Wang ◽  
Maria Spatz ◽  
Gregory J del Zoppo
Keyword(s):  
Cerebral Ischemia ◽  
Basal Lamina ◽  
Focal Cerebral Ischemia ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Receptor Expression ◽  
Cerebral Microvessels ◽  
The Impact

During focal cerebral ischemia, the detachment of astrocytes from the microvascular basal lamina is not completely explained by known integrin receptor expression changes. Here, the impact of experimental ischemia (oxygen—glucose deprivation (OGD)) on dystroglycan expression by murine endothelial cells and astrocytes grown on vascular matrix laminin, perlecan, or collagen and the impact of middle cerebral artery occlusion on αβ-dystroglycan within cerebral microvessels of the nonhuman primate were examined. Dystroglycan was expressed on all cerebral microvessels in cortical gray and white matter, and the striatum. Astrocyte adhesion to basal lamina proteins was managed in part by α-dystroglycan, while ischemia significantly reduced expression of dystroglycan both in vivo and in vitro. Furthermore, dystroglycan and integrin α6β4 expressions on astrocyte end-feet decreased in parallel both in vivo and in vitro. The rapid loss of astrocyte dystroglycan during OGD appears protease-dependent, involving an matrix metalloproteinase-like activity. This may explain the rapid detachment of astrocytes from the microvascular basal lamina during ischemic injury, which could contribute to significant changes in microvascular integrity.

scholarly journals MicroRNA-30a regulates acute cerebral ischemia-induced blood–brain barrier damage through ZnT4/zinc pathway

2020 ◽  
pp. 0271678X2092678 ◽  
Author(s):  
Peng Wang ◽  
Rong Pan ◽  
John Weaver ◽  
Mengjie Jia ◽  
Xue Yang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Tight Junction Proteins ◽  
Blood Brain ◽  
Acute Cerebral Ischemia ◽  
Junction Proteins

The mechanism of early blood–brain barrier (BBB) disruption after stroke has been intensively studied but still not fully understood. Here, we report that microRNA-30a (miR-30a) could mediate BBB damage using both cellular and animal models of ischemic stroke. In the experiments in vitro, inhibition of miR-30a decreased BBB permeability, prevented the degradation of tight junction proteins, and reduced intracellular free zinc in endothelial cells. We found that the zinc transporter ZnT4 was a direct target of negative regulation by miR-30a, and ZnT4/zinc signaling pathway contributed significantly to miR-30a-mediated BBB damage. Consistent with these in vitro findings, treatment with miR-30a inhibitor reduced zinc accumulation, increased the expression of ZnT4, and prevented the loss of tight junction proteins in microvessels of ischemic animals. Furthermore, inhibition of miR-30a, even at 90 min post onset of middle cerebral artery occlusion, prevented BBB damage, reduced infarct volume, and ameliorated neurological deficits. Together, our findings provide novel insights into the mechanisms of cerebral ischemia-induced BBB disruption and indicate miR-30a as a regulator of BBB function that can be an effective therapeutic target for ischemic stroke.

Sign in / Sign up

Export Citation Format

Share Document