scholarly journals Angiogenesis in the ischemic core: A potential treatment target?

2019 ◽  
Vol 39 (5) ◽  
pp. 753-769 ◽  
Author(s):  
Masato Kanazawa ◽  
Tetsuya Takahashi ◽  
Masanori Ishikawa ◽  
Osamu Onodera ◽  
Takayoshi Shimohata ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Tissue Injury ◽  
Focal Cerebral Ischemia ◽  
Neurovascular Unit ◽  
Focal Ischemia ◽  
Model Systems ◽  
Surrounding Tissue ◽  
Model Studies ◽  
Ischemic Core

The ischemic penumbra is both a concept in understanding the evolution of cerebral tissue injury outcome of focal ischemia and a potential therapeutic target for ischemic stroke. In this review, we examine the evidence that angiogenesis can contribute to beneficial outcomes following focal ischemia in model systems. Several studies have shown that, following cerebral ischemia, endothelial proliferation and subsequent angiogenesis can be detected beginning four days after cerebral ischemia in the border of the ischemic core, or in the ischemic periphery, in rodent and non-human primate models, although initial signals appear within hours of ischemia onset. Components of the neurovascular unit, its participation in new vessel formation, and the nature of the core and penumbra responses to experimental focal cerebral ischemia, are considered here. The potential co-localization of vascular remodeling and axonal outgrowth following focal cerebral ischemia based on the definition of tissue remodeling and the processes that follow ischemic stroke are also considered. The region of angiogenesis in the ischemic core and its surrounding tissue (ischemic periphery) may be a novel target for treatment. We summarize issues that are relevant to model studies of focal cerebral ischemia looking ahead to potential treatments.

Abstract 3866: The Inhibition of WWP-1 and Activation of AMPKa2 Are Important Mediators of Ischemic Stroke

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Yong-Joo Ahn ◽  
Jung Ok Lee ◽  
Seo-Kyoung Hwang ◽  
Hyeon Soo Kim ◽  
James K. Liao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Infarct Size ◽  
Signaling Pathways ◽  
Focal Cerebral Ischemia ◽  
Mtor Signaling ◽  
Cerebral Infarct ◽  
Acute Administration ◽  
Therapeutic Benefits ◽  
Ischemic Core

Background: Tuberous sclerosis complex (TSC) and Mammalian target of rapamycin (mTOR) mediate various functions such as cell survival, obesity, and cellular responses in injury. However, the signaling mechanism linking focal cerebral ischemia is unknown. Because inhibition of the mTOR signaling pathway contributes to the pathogenesis of ischemic stroke, we hypothesize that inhibition of WW domain protein 1 (WWP-1) and activation of AMPKα2 mediate neuroprotection effect via WWP-1/AMPKα2/TSC/mTOR/S6 signaling pathways. Methods: To investigate whether the inhibition of WWP-1 and activation of AMPKα2 could exert neuroprotective effect via mTOR signaling pathways, we performed transient focal cerebral ischemia. Wild-type and TSC2 +− mice (20-22g) were administered either vehicle or rapamycin (5 mg/kg, i.p., 1d and 5d), before MCAO. After 2 hrs of MCAO followed by 22 hrs of reperfusion, Infarct size was determined with TTC staining and protein levels were assessed in ischemic core and contralateral (non-ischemic core) hemisphere region. Results: Compare to vehicle mice, mTOR/S6 level was decreased in ischemic brain region during ischemia (0.5, 1, 2h MCAO). After reperfusion (after 2h MCAO), phospho-S6 in mice brain was quickly over-expressed. Acute administration of rapamycin had no effect on cerebral infarct size in WT mice but chronic administration of rapamycin exhibited significantly increased infarct size and higher NDS following MCAO. Compare to vehicle mice, TSC2 +− mice showed increased mTOR/S6 level in brain and reduced cerebral infarct size (64.2 ± 5.96; n =7 vs 92.6 ± 6.08, n =7, p <0.01). Conclusions: These findings indicate that the inhibition of WWP-1 and activation of AMPKα2 reduced infarct size via TSC2/mTOR/S6 signal transduction in focal cerebral ischemia. These results suggest that inhibition of WWP-1 and activation of AMPKα2 may have therapeutic benefits in ischemic stroke.

scholarly journals Brief Focal Cerebral Ischemia That Simulates Transient Ischemic Attacks in Humans Regulates Gene Expression in Rat Peripheral Blood

2009 ◽  
Vol 30 (1) ◽  
pp. 110-118 ◽  
Author(s):  
Xinhua Zhan ◽  
Bradley P Ander ◽  
Glen Jickling ◽  
Renée Turner ◽  
Boryana Stamova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Peripheral Blood ◽  
Focal Cerebral Ischemia ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Focal Ischemia ◽  
Transient Ischemic Attacks

Blood gene expression profiles of very brief (5 and 10 mins) focal ischemia that simulates transient ischemic attacks in humans were compared with ischemic stroke (120 mins focal ischemia), sham, and naïve controls. The number of significantly regulated genes after 5 and 10 mins of cerebral ischemia was 39 and 160, respectively (fold change ⩾∣1.5∣ and P<0.05). There were 103 genes common to brief focal ischemia and ischemic stroke. Ingenuity pathway analysis showed that genes regulated in the 5 mins group were mainly involved in small molecule biochemistry. Genes regulated in the 10 mins group were involved in cell death, development, growth, and proliferation. Such genes were also regulated in the ischemic stroke group. Genes common to ischemia were involved in the inflammatory response, immune response, and cell death—indicating that these pathways are a feature of focal ischemia, regardless of the duration. These results provide evidence that brief focal ischemia differentially regulates gene expression in the peripheral blood in a manner that could distinguish brief focal ischemia from ischemic stroke and controls in rats. We postulate that this will also occur in humans.

scholarly journals Cathepsin L Acutely Alters Microvessel Integrity within the Neurovascular Unit during Focal Cerebral Ischemia

2015 ◽  
Vol 35 (11) ◽  
pp. 1888-1900 ◽  
Author(s):  
Yu-Huan Gu ◽  
Masato Kanazawa ◽  
Stephanie Y Hung ◽  
Xiaoyun Wang ◽  
Shunichi Fukuda ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cerebral Ischemia ◽  
Ex Vivo ◽  
Focal Cerebral Ischemia ◽  
Cathepsin L ◽  
Neurovascular Unit ◽  
Edema Formation ◽  
Ischemic Core ◽  
Neuron Injury

During focal cerebral ischemia, the degradation of microvessel basal lamina matrix occurs acutely and is associated with edema formation and microhemorrhage. These events have been attributed to matrix metalloproteinases (MMPs). However, both known protease generation and ligand specificities suggest other participants. Using cerebral tissues from a non-human primate focal ischemia model and primary murine brain endothelial cells, astrocytes, and microglia in culture, the effects of active cathepsin L have been defined. Within 2 hours of ischemia onset cathepsin L, but not cathepsin B, activity appears in the ischemic core, around microvessels, within regions of neuron injury and cathepsin L expression. In in vitro studies, cathepsin L activity is generated during experimental ischemia in microglia, but not astrocytes or endothelial cells. In the acidic ischemic core, cathepsin L release is significantly increased with time. A novel ex vivo assay showed that cathepsin L released from microglia during ischemia degrades microvessel matrix, and interacts with MMP activity. Hence, the loss of microvessel matrix during ischemia is explained by microglial cathepsin L release in the acidic core during injury evolution. The roles of cathepsin L and its interactions with specific MMP activities during ischemia are relevant to strategies to reduce microvessel injury and hemorrhage.

scholarly journals Cellular and Molecular Mechanisms of R/S-Roscovitine and CDKs Related Inhibition under Both Focal and Global Cerebral Ischemia: A Focus on Neurovascular Unit and Immune Cells

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 104
Author(s):  
Lucas Le Roy ◽  
Anne Letondor ◽  
Cloé Le Roux ◽  
Ahmed Amara ◽  
Serge Timsit
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Molecular Mechanisms ◽  
Focal Cerebral Ischemia ◽  
Neurovascular Unit ◽  
Brain Lesions ◽  
Global Cerebral Ischemia ◽  
Inflammatory Models ◽  
Long Time ◽  
Inflammatory Processes

Ischemic stroke is the second leading cause of death worldwide. Following ischemic stroke, Neurovascular Unit (NVU) inflammation and peripheral leucocytes infiltration are major contributors to the extension of brain lesions. For a long time restricted to neurons, the 10 past years have shown the emergence of an increasing number of studies focusing on the role of Cyclin-Dependent Kinases (CDKs) on the other cells of NVU, as well as on the leucocytes. The most widely used CDKs inhibitor, (R)-roscovitine, and its (S) isomer both decreased brain lesions in models of global and focal cerebral ischemia. We previously showed that (S)-roscovitine acted, at least, by modulating NVU response to ischemia. Interestingly, roscovitine was shown to decrease leucocytes-mediated inflammation in several inflammatory models. Specific inhibition of roscovitine majors target CDK 1, 2, 5, 7, and 9 showed that these CDKs played key roles in inflammatory processes of NVU cells and leucocytes after brain lesions, including ischemic stroke. The data summarized here support the investigation of roscovitine as a potential therapeutic agent for the treatment of ischemic stroke, and provide an overview of CDK 1, 2, 5, 7, and 9 functions in brain cells and leucocytes during cerebral ischemia.

scholarly journals Microtubular Proteolysis in Focal Cerebral Ischemia

1996 ◽  
Vol 16 (6) ◽  
pp. 1189-1202 ◽  
Author(s):  
L. Creed Pettigrew ◽  
Mary L. Holtz ◽  
Susan D. Craddock ◽  
Stephen L. Minger ◽  
Nathan Hall ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Tissue Injury ◽  
Focal Cerebral Ischemia ◽  
Significant Loss ◽  
Calpain Activity ◽  
Infarct Zone ◽  
Ischemic Brain ◽  
Τ Protein ◽  
Map2 Immunoreactivity ◽  
Apical Dendrites

Calpain, a neutral protease activated by calcium, may promote microtubular proteolysis in ischemic brain. We tested this hypothesis in an animal model of focal cerebral ischemia without reperfusion. The earliest sign of tissue injury was observed after no more than 15 min of ischemia, with coiling of apical dendrites immunolabeled to show microtubule-associated protein 2 (MAP2). After 6 h of ischemia, MAP2 immunoreactivity was markedly diminished in the infarct zone. Quantitative Western analysis demonstrated that MAP2 was almost unmeasurable after 24 h of ischemia. An increase in calpain activity, shown by an antibody recognizing calpain-cleaved spectrin fragments, paralleled the loss of MAP2 immunostaining. Double-labeled immunofluorescent studies showed that intraneuronal calpain activity preceded evidence of MAP2 proteolysis. Perikaryal immunolabeling of τ protein became increasingly prominent between 1 and 6 h in neurons located within the transition zone between ischemic and unaffected tissue. Western blot experiments confirmed that dephosphorylation of τ protein occurred during 24 h of ischemia, but was not associated with significant loss of τ antigen. We conclude that focal cerebral ischemia is associated with early microtubular proteolysis caused by calpain.

scholarly journals Tissue Acidosis Associated with Ischemic Stroke to Guide Neuroprotective Drug Delivery

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 460
Author(s):  
Orsolya M. Tóth ◽  
Ákos Menyhárt ◽  
Rita Frank ◽  
Dóra Hantosi ◽  
Eszter Farkas ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Targeted Delivery ◽  
Focal Cerebral Ischemia ◽  
Ischemic Penumbra ◽  
Risk Of Injury ◽  
Ischemic Tissue ◽  
Tissue Acidosis ◽  
Injury Progression

Ischemic stroke is a leading cause of death and disability worldwide. Yet, the effective therapy of focal cerebral ischemia has been an unresolved challenge. We propose here that ischemic tissue acidosis, a sensitive metabolic indicator of injury progression in cerebral ischemia, can be harnessed for the targeted delivery of neuroprotective agents. Ischemic tissue acidosis, which represents the accumulation of lactic acid in malperfused brain tissue is significantly exacerbated by the recurrence of spreading depolarizations. Deepening acidosis itself activates specific ion channels to cause neurotoxic cellular Ca2+ accumulation and cytotoxic edema. These processes are thought to contribute to the loss of the ischemic penumbra. The unique metabolic status of the ischemic penumbra has been exploited to identify the penumbra zone with imaging tools. Importantly, acidosis in the ischemic penumbra may also be used to guide therapeutic intervention. Agents with neuroprotective promise are suggested here to be delivered selectively to the ischemic penumbra with pH-responsive smart nanosystems. The administered nanoparticels release their cargo in acidic tissue environment, which reliably delineates sites at risk of injury. Therefore, tissue pH-targeted drug delivery is expected to enrich sites of ongoing injury with the therapeutical agent, without the risk of unfavorable off-target effects.

scholarly journals Transcriptomic characterization of microglia activation in a rat model of ischemic stroke

2020 ◽  
Vol 40 (1_suppl) ◽  
pp. S34-S48
Author(s):  
Wenjun Deng ◽  
Emiri Mandeville ◽  
Yasukazu Terasaki ◽  
Wenlu Li ◽  
Julie Holder ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Phenotypic Diversity ◽  
Focal Cerebral Ischemia ◽  
Wide Spectrum ◽  
Spontaneously Hypertensive ◽  
Transient Focal Cerebral Ischemia ◽  
Microglial Response ◽  
Whole Transcriptome

Microglia are key regulators of inflammatory response after stroke and brain injury. To better understand activation of microglia as well as their phenotypic diversity after ischemic stroke, we profiled the transcriptome of microglia after 75 min transient focal cerebral ischemia in 3-month- and 12-month-old male spontaneously hypertensive rats. Microglia were isolated from the brains by FACS sorting on days 3 and 14 after cerebral ischemia. GeneChip Rat 1.0ST microarray was used to profile the whole transcriptome of sorted microglia. We identified an evolving and complex pattern of activation from 3 to 14 days after stroke onset. M2-like patterns were extensively and persistently upregulated over time. M1-like patterns were only mildly upregulated, mostly at day 14. Younger 3-month-old brains showed a larger microglial response in both pro- and anti-inflammatory pathways, compared to older 12-month-old brains. Importantly, our data revealed that after stroke, most microglia are activated towards a wide spectrum of novel polarization states beyond the standard M1/M2 dichotomy, especially in pathways related to TLR2 and dietary fatty acid signaling. Finally, classes of transcription factors that might potentially regulate microglial activation were identified. These findings should provide a comprehensive database for dissecting microglial mechanisms and pursuing neuroinflammation targets for acute ischemic stroke.

scholarly journals Modulation by Nitric Oxide of Cerebral Neutrophil Accumulation after Transient Focal Ischemia in Rats

2000 ◽  
Vol 20 (5) ◽  
pp. 812-819 ◽  
Author(s):  
Sophie Batteur-Parmentier ◽  
Isabelle Margaill ◽  
Michel Plotkine
Keyword(s):  
Nitric Oxide ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neutrophil Infiltration ◽  
Focal Ischemia ◽  
Left Middle Cerebral Artery ◽  
No Production ◽  
Myeloperoxidase Activity ◽  
Transient Focal Ischemia

A beneficial role of nitric oxide (NO) after cerebral ischemia has been previously attributed to its vascular effects. Recent data indicate a regulatory role for NO in initial leukocyte-endothelial interactions in the cerebral microcirculation under basal and ischemic conditions. In this study, the authors tested the hypothesis that endogenous NO production during and/or after transient focal cerebral ischemia can also be neuroprotective by limiting the process of neutrophil infiltration and its deleterious consequences. Male Sprague-Dawley rats were subjected to 2 hours occlusion of the left middle cerebral artery and the left common carotid artery. The effect of NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg, intraperitoneally), an NO synthase inhibitor, was examined at 48 hours after ischemia on both infarct size and myeloperoxidase activity, an index of neutrophil infiltration. L-NAME given 5 minutes after the onset of ischemia increased the cortical infarct volume by 34% and increased cortical myeloperoxidase activity by 60%, whereas administration of L-NAME at 1, 7, and 22 hours of reperfusion had no effect. Such exacerbations of infarction and myeloperoxidase activity produced when L-NAME was given 5 minutes after the onset of ischemia were not observed in rats rendered neutropenic by vinblastine. These results suggest that after transient focal ischemia, early NO production exerts a neuroprotective effect by modulating neutrophil infiltration.

Sign in / Sign up

Export Citation Format

Share Document