Experimental models of focal and multifocal cerebral ischemia: a review

2018 ◽  
Vol 29 (6) ◽  
pp. 661-674 ◽  
Author(s):  
Kristy L. Meadows
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Treatment Options ◽  
Experimental Models ◽  
Preclinical Research ◽  
Stroke Research ◽  
Naturally Occurring ◽  
Tissue Plasminogen ◽  
Stroke Models

AbstractRodent and rabbit stroke models have been instrumental in our current understanding of stroke pathophysiology; however, translational failure is a significant problem in preclinical ischemic stroke research today. There are a number of different focal cerebral ischemia models that vary in their utility, pathophysiology of causing disease, and their response to treatments. Unfortunately, despite active preclinical research using these models, treatment options for ischemic stroke have not significantly advanced since the food and drug administration approval of tissue plasminogen activator in 1996. This review aims to summarize current stroke therapies, the preclinical experimental models used to help develop stroke therapies, as well as their advantages and limitations. In addition, this review discusses the potential for naturally occurring canine ischemic stroke models to compliment current preclinical models and to help bridge the translational gap between small mammal models and human clinical trials.

scholarly journals Knockout of Silent Information Regulator 2 (SIRT2) Preserves Neurological Function after Experimental Stroke in Mice

2015 ◽  
Vol 35 (12) ◽  
pp. 2080-2088 ◽  
Author(s):  
Lea Krey ◽  
Fred Lühder ◽  
Kathrin Kusch ◽  
Bozena Czech-Zechmeister ◽  
Birte Könnecke ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Brain Regions ◽  
Artery Occlusion ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Wild Type ◽  
Significant Difference ◽  
Stroke Models

Sirtuin-2 (Sirt2) is a member of the NAD+-dependent protein deacetylase family. Various members of the sirtuin class have been found to be involved in processes related to longevity, regulation of inflammation, and neuroprotection. Induction of Sirt2 mRNA was found in the whole hemisphere after experimental stroke in a recent screening approach. Moreover, Sirt2 protein is highly expressed in myelin-rich brain regions after stroke. To examine the effects of Sirt2 on ischemic stroke, we induced transient focal cerebral ischemia in adult male Sirt2-knockout and wild-type mice. Two stroke models with different occlusion times were applied: a severe ischemia (45 minutes of middle cerebral artery occlusion (MCAO)) and a mild one (15 minutes of MCAO), which was used to focus on subcortical infarcts. Neurological deficit was determined at 48 hours after 45 minutes of MCAO, and up to 7 days after induction of 15 minutes of cerebral ischemia. In contrast to recent data on Sirt1, Sirt2−/− mice showed less neurological deficits in both models of experimental stroke, with the strongest manifestation after 48 hours of reperfusion. However, we did not observe a significant difference of stroke volumes or inflammatory cell count between Sirt2-deficient and wild-type mice. Thus we postulate that Sirt2 mediates myelin-dependent neuronal dysfunction during the early phase after ischemic stroke.

SMI-32 — a novel axonal injury marker for investigation of ischemic brain pathology

2021 ◽  
Vol 20 (4) ◽  
pp. 63-68
Author(s):  
Daria L. Tsyba ◽  
Olga V. Kirik ◽  
Dmitrii E. Korzhevskii
Keyword(s):  
Cerebral Ischemia ◽  
Heavy Chain ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Axonal Injury ◽  
Experimental Models ◽  
Nerve Fibers ◽  
Left Middle Cerebral Artery ◽  
Social Significance ◽  
Neurofilament Proteins

The relevance of this work is determined by the high prevalence and social significance of cerebrovascular diseases and the need to develop effective methods for verifying neuronal damage due to cerebral ischemia in experimental models. The aim of this study was to assess the possibility of immunohistochemical revealing of neurofilaments to detect axonal injury in cerebral ischemia models. Materials and methods. A model of transient focal cerebral ischemia by the left middle cerebral artery occlusion was reproduced in male Wistar, SHR and WKY rats. Axonal injury was assessed by immunohistochemical reactions for neurofilament proteins using SMI-32 and 2F11 antibodies. Results. In cerebral ischemia, damage to nerve fibers occurs, manifested by thickening of axons, their varicose expansion and segmental accumulation of neurofilament proteins. These changes are more noticeable with an immunohistochemical reaction to the SMI-32 marker of neurofilament heavy chain. Conclusions. The use of antibodies to the non-phosphorylated neurofilament heavy chain makes it easy to identify degenerating nerve fibers and can be recommended as an alternative method for detecting axonal injury.

A Review on Preclinical Models of Ischemic Stroke: Insights Into the Pathomechanisms and New Treatment Strategies

2021 ◽  
Vol 19 ◽  
Author(s):  
Aditya A Singh ◽  
Akash Kharwar ◽  
Manoj P. Dandekar
Keyword(s):  
Stem Cell ◽  
Ischemic Stroke ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Neurotrophic Factors ◽  
Treatment Strategies ◽  
Experimental Models ◽  
Cerebral Stroke ◽  
Post Stroke ◽  
Stroke Models

Background: Stroke is a serious neurovascular problem and the leading cause of disability and death worldwide. The disrupted demand to supply ratio of blood and glucose during cerebral ischemia develops hypoxic shock, and subsequently necrotic neuronal death in the affected regions. Multiple causal factors like age, sex, race, genetics, diet, and lifestyle play an important role in the occurrence as well as progression of post-stroke deleterious events. These biological and environmental factors may be contributed to vasculature variable architecture and abnormal neuronal activity. Since recombinant tissue plasminogen activator is the only clinically effective clot bursting drug, there is a huge unmet medical need for newer therapies for the treatment of stroke. Innumerous therapeutic interventions have shown promise in the experimental models of stroke but failed to translate it into clinical counterparts. Methods: Original publications regarding pathophysiology, preclinical experimental models, new targets and therapies targeting ischemic stroke have been reviewed since the 1970s. Results: We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Results : We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Conclusion: There are still many inter-linked pathophysiological alterations with regards to stroke, animal models need not necessarily mimic the same conditions of stroke pathology and newer targets and therapies are the need of the hour in stroke research.

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.

VWF-Cleaving Protease ADAMTS13 Reduces Brain Injury Following Ischemic Stroke in Mice: Essential Role for VWF in Stroke

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 259-259
Author(s):  
Bing-Qiao Zhao ◽  
Anil kumar Chauhan ◽  
Ian S. Patten ◽  
Michael Dockal ◽  
Friedrich Scheiflinger ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Essential Role ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Recombinant Tissue Plasminogen Activator ◽  
Protective Role ◽  
Artery Occlusion ◽  
Type I ◽  
Deficient Mice

Abstract Ischemic stroke is the second leading cause of death and disability. The only approved therapy available is recombinant tissue plasminogen activator (tPA), but its use remains limited. Therefore, there is a need for an alternative drug. Platelets and their adhesion receptors play a crucial role in modulating infarct size during ischemic stroke. ADAMTS13 (A Disintegrin-like And Metalloprotease with Thrombospondin type I repeats-13) is a plasma metalloprotease that cleaves von Willebrand factor (VWF) an important adhesion molecule for platelets at sites of vascular injury. In patients, an increase in circulating levels of VWF and a decrease in ADAMTS13 activity are considered risk factors for ischemic stroke. By using genetically-modified mice we have previously shown that ADAMTS13 down regulates both thrombosis and inflammation and recombinant human ADAMTS13 down regulates platelet thrombi in injured arterioles. All these processes were dependent on VWF. We therefore hypothesize that ADAMTS13 has a protective role after ischemic stroke. In this study, we show that VWF deficiency or VWF heterozygosity in mice reduces infarct volume by two-fold after focal cerebral ischemia compared to wild-type (WT) in the middle cerebral artery occlusion (MCAO) stroke model. Furthermore, infusion of recombinant human VWF in WT mice not only accelerates thrombosis in the ferric-chloride injured artery model, but also increases infarct volume compared to vehicle-treated controls. These findings suggest an essential role of VWF in modulating infarction after stroke. We also show that ADAMTS13 deficiency in mice results in approximately 20% larger infarcts after cerebral ischemia compared to WT. The larger infarcts observed in ADAMTS13 deficient mice were due to VWF because mice deficient in both ADAMTS13 and VWF had infarct sizes similar to VWF deficient mice. Importantly, infusion of r-human ADAMTS13 immediately before reperfusion (two hour after occlusion) significantly reduced infarct volume (106.2 ± 9.7 mm3 vs 75.8 ± 6.9 mm3, P<0.05). Of note, we observed that ADAMTS13 protein was induced in the ischemic penumbra region of brain after ischemic stroke. Our findings reveal an important role for VWF in modulating infarct volume after ischemic stroke. In addition, recombinant-ADAMTS13 could become a new therapeutic agent for stroke therapy.

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