Acute ischemic stroke: Overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia

2007 ◽  
Vol 87 (1) ◽  
pp. 179-197 ◽  
Author(s):  
Aysan Durukan ◽  
Turgut Tatlisumak
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Focal Cerebral Ischemia ◽  
Rodent Models

scholarly journals A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia

2000 ◽  
Vol XXXII (3-4) ◽  
pp. 76-76
Author(s):  
J. Yrjanheikki ◽  
T. Tikka ◽  
R. Keinanen ◽  
G. Goldsteins ◽  
P. H. Chan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Brain Tissue ◽  
Focal Cerebral Ischemia ◽  
The Brain ◽  
Tetracycline Derivative

One of the reasons for the insufficient effectiveness of treatment of acute ischemic stroke may be secondary inflammation of the brain tissue, which, according to the results of modern studies, significantly worsens the consequences and outcome of the disease.

scholarly journals Mucosal‐Associated Invariant T Cells Are Involved in Acute Ischemic Stroke by Regulating Neuroinflammation

2021 ◽  
Author(s):  
Sho Nakajima ◽  
Ryota Tanaka ◽  
Kazuo Yamashiro ◽  
Asako Chiba ◽  
Daisuke Noto ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Flow Cytometric Analysis ◽  
Interleukin 17 ◽  
Ischemic Brain ◽  
Mait Cells ◽  
Acute Cerebral Ischemia

Background Mucosal‐associated invariant T (MAIT) cells have been associated with inflammation in several autoimmune diseases. However, their relation to ischemic stroke remains unclear. This study attempted to elucidate the role of MAIT cells in acute ischemic stroke in mice. Methods and Results We used MR1 knockout C57BL/6 (MR1 −/− ) mice and wild‐type littermates (MR1 +/+ ). After performing a transient middle cerebral artery occlusion (tMCAO), we evaluated the association with inflammation and prognosis in the acute cerebral ischemia. Furthermore, we analyzed the tMCAO C57BL/6 mice administered with the suppressive MR1 ligand and the vehicle control. We also evaluated the infiltration of MAIT cells into the ischemic brain by flow cytometry. Results showed a reduction of infarct volume and an improvement of neurological impairment in MR1 −/− mice (n=8). There was a reduction in the number of infiltrating microglia/macrophages (n=3–5) and in their activation (n=5) in the peri‐infarct area of MR1 −/− mice. The cytokine levels of interleukin‐6 and interleukin‐17 at 24 hours after tMCAO (n=3–5), and for interleukin‐17 at 72 hours after tMCAO (n=5), were lower in the MR1 −/− mice. The administration of the suppressive MR1 ligand reduced the infarct volume and improved functional impairment (n=5). Flow cytometric analysis demonstrated there was a reduction of MAIT cells infiltrating into the ischemic brain at 24 hours after tMCAO (n=17). Conclusions Our results showed that MAIT cells play an important role in neuroinflammation after focal cerebral ischemia and the use of MAIT cell regulation has a potential role as a novel neuroprotectant for the treatment of acute ischemic stroke.

scholarly journals Human-Albumin Neuroprotection in Acute Ischemic Stroke: Marked Efficacy at Moderate Doses, with a Broad Therapeutic Window.

Stroke ◽  
2001 ◽  
Vol 32 (suppl_1) ◽  
pp. 326-326
Author(s):  
Myron D Ginsberg ◽  
Ludmila Belayev ◽  
Yitao Liu ◽  
Weizhao Zhao ◽  
Raul Busto
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Human Albumin ◽  
Global Cerebral Ischemia ◽  
Therapeutic Window ◽  
High Dose ◽  
Neurological Score

58 We have previously shown that high-dose human albumin (Alb) is markedly neuroprotective in focal and global cerebral ischemia and in traumatic brain injury. In this study, we examined the efficacy of moderate, clinically achievable Alb doses and defined the therapeutic window in focal cerebral ischemia. Sprague Dawley rats (n=62) were anesthetized with halothane/nitrous oxide and received 2-h middle cerebral artery occlusion (MCAo) by intraluminal suture. Neurological status was evaluated during occlusion (60 min) and daily for 3 days after MCAo. In the dose-response study, animals were given either 25% Alb in doses 0.63 or 1.25 g/kg , or 0.9% saline vehicle, i.v. immediately after suture removal (n=5 each). In the therapeutic window study, 1.25 g/kg Alb was administered at either 2 h, 3 h, 4 h, or 5 h after onset of stroke (i.e., 0 to 3 h after onset of reperfusion) (n=9–10 ea.). Three days after MCAo, brains were perfusion-fixed, and image-processing was used to compute infarct volumes and brain swelling. Both moderate Alb doses (0.63 and 1.25 g/kg) significantly improved the neurological score compared to vehicle rats at 24h, 48h and 72h; and markedly reduced cortical infarct volume (by 66±14% and 95±4%, respectively), striatal infarct volume (by 54±8% and 52±14%), and total infarct volume (by 58±5% and 67±9%, respectively). Brain edema was virtually eliminated by Alb treatment. In the therapeutic window study, even when treatment was initiated as late as 4 hours after onset of MCAo, 1.25 g/kg Alb led to significantly improved neurological score and highly significant reductions of infarct areas in cortex (68% reduction), subcortical regions (52% reduction), and total infarct (61% reduction). The striking efficacy and broad therapeutic window of moderate-dose Alb therapy in experimental focal ischemia strongly supports the feasibility of initiating early-phase clinical trials of this promising agent in patients with acute ischemic stroke. This work was supported by NIH Grant NS05820 (MDG) and by AHA Initial Investigator Award (LB).

scholarly journals Hypothermic neuroprotection against acute ischemic stroke: The 2019 update

2019 ◽  
Vol 40 (3) ◽  
pp. 461-481 ◽  
Author(s):  
Longfei Wu ◽  
Di Wu ◽  
Tuo Yang ◽  
Jin Xu ◽  
Jian Chen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Brain Injuries ◽  
Focal Cerebral Ischemia ◽  
Global Cerebral Ischemia ◽  
Neuroprotective Effects ◽  
Neuroprotective Strategies ◽  
Selective Cooling ◽  
Ischemic Encephalopathy

Acute ischemic stroke is a leading cause of death and disability worldwide. Therapeutic hypothermia has long been considered as one of the most robust neuroprotective strategies. Although the neuroprotective effects of hypothermia have only been confirmed in patients with global cerebral ischemia after cardiac arrest and in neonatal hypoxic ischemic encephalopathy, establishing standardized protocols and strictly controlling the key parameters may extend its application in other brain injuries, such as acute ischemic stroke. In this review, we discuss the potential neuroprotective effects of hypothermia, its drawbacks evidenced in previous studies, and its potential clinical application for acute ischemic stroke especially in the era of reperfusion. Based on the different conditions between bench and bedside settings, we demonstrate the importance of vascular recanalization for neuroprotection of hypothermia by analyzing numerous literatures regarding hypothermia in focal cerebral ischemia. Then, we make a thorough analysis of key parameters of hypothermia and introduce novel hypothermic therapies. We advocate in favor of the process of clinical translation of intra-arterial selective cooling infusion in the era of reperfusion and provide insights into the prospects of hypothermia in acute ischemic stroke.

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.

Neuroprotective effect of ginkgolide K against acute ischemic stroke on middle cerebral ischemia occlusion in rats

2011 ◽  
Vol 66 (1) ◽  
pp. 25-31 ◽  
Author(s):  
Shuwei Ma ◽  
Huafeng Yin ◽  
Lvyi Chen ◽  
Hongxia Liu ◽  
Ming Zhao ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Neuroprotective Effect

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 Catheter based selective hypothermia reduces stroke volume during focal cerebral ischemia in swine

2015 ◽  
Vol 8 (4) ◽  
pp. 418-422 ◽  
Author(s):  
Thomas K Mattingly ◽  
Lynn M Denning ◽  
Karen L Siroen ◽  
Barb Lehrbass ◽  
Pablo Lopez-Ojeda ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Stroke Volume ◽  
Acute Ischemic Stroke ◽  
Brain Mri ◽  
Global Cerebral Ischemia ◽  
Moderate Hypothermia ◽  
Stroke Model ◽  
Stroke Treatment ◽  
Endovascular Cooling

BackgroundTotal body hypothermia is an established neuroprotectant in global cerebral ischemia. The role of hypothermia in acute ischemic stroke remains uncertain. Selective application of hypothermia to a region of focal ischemia may provide similar protection with more rapid cooling and elimination of systemic side effects. We studied the effect of selective endovascular cooling in a focal stroke model in adult domestic swine.MethodsAfter craniotomy under general anesthesia, a proximal middle cerebral artery branch was occluded for 3 h, followed by 3 h of reperfusion. In half of the animals, selective hypothermia was induced during reperfusion using a dual lumen balloon occlusion catheter placed in the ipsilateral common carotid artery. Following reperfusion, the animals were sacrificed. Brain MRI and histology were evaluated by experts who were blinded to the intervention.Results25 animals were available for analysis. Using selective hypothermia, hemicranial temperature was successfully cooled to a mean of 26.5°C. Average time from start of perfusion to attainment of moderate hypothermia (<30°C) was 25 min. Mean MRI stroke volumes were significantly reduced by selective cooling (0.050±0.059 control, 0.005±0.011 hypothermia (ratio stroke:hemisphere volume) (p=0.046). Stroke pathology volumes were reduced by 42% compared with controls (p=0.256).ConclusionsSelective moderate hypothermia was rapidly induced using endovascular techniques in a clinically realistic swine stroke model. A significant reduction in stroke volume on MRI was observed. Endovascular selective hypothermia can provide neuroprotection within time frames relevant to acute ischemic stroke treatment.

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&lt;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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