scholarly journals Interstitial pO2 in Ischemic Penumbra and Core are Differentially Affected following Transient Focal Cerebral Ischemia in Rats

2004 ◽  
Vol 24 (3) ◽  
pp. 343-349 ◽  
Author(s):  
Shimin Liu ◽  
Honglian Shi ◽  
Wenlan Liu ◽  
Takamitsu Furuichi ◽  
Graham S Timmins ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Focal Cerebral Ischemia ◽  
Ischemia And Reperfusion ◽  
Interstitial Oxygen ◽  
Ischemic Penumbra ◽  
Irreversible Damage ◽  
Paramagnetic Resonance ◽  
Consumption Rates

Stroke causes heterogeneous changes in tissue oxygenation, with a region of decreased blood flow, the penumbra, surrounding a severely damaged ischemic core. Treatment of acute ischemic stroke aims to save this penumbra before its irreversible damage by continued ischemia. However, effective treatment remains elusive due to incomplete understanding of processes leading to penumbral death. While oxygenation is central in ischemic neuronal death, it is unclear exactly what actual changes occur in interstitial oxygen tension (pO2) in ischemic regions during stroke, particularly the penumbra. Using the unique capability of in vivo electron paramagnetic resonance (EPR) oximetry to measure localized interstitial pO2, we measured both absolute values, and temporal changes of pO2 in ischemic penumbra and core during ischemia and reperfusion in a rat model. Ischemia rapidly decreased interstitial pO2 to 32% ± 7.6% and 4% ± 0.6% of pre-ischemic values in penumbra and core, respectively 1 hour after ischemia. Importantly, whilst reperfusion restored core pO2 close to its pre-ischemic value, penumbral pO2 only partially recovered. Hyperoxic treatment significantly increased penumbral pO2 during ischemia, but not in the core, and also increased penumbral pO2 during reperfusion. These divergent, important changes in pO2 in penumbra and core were explained by combined differences in cellular oxygen consumption rates and microcirculation conditions. We therefore demonstrate that interstitial pO2 in penumbra and core is differentially affected during ischemia and reperfusion, providing new insights to the pathophysiology of stroke. The results support normobaric hyperoxia as a potential early intervention to save penumbral tissue in acute ischemic stroke.

scholarly journals Ischemic Penumbra: Evidence From Functional Imaging in Man

2000 ◽  
Vol 20 (9) ◽  
pp. 1276-1293 ◽  
Author(s):  
Wolf-Dieter Heiss
Keyword(s):  
Computed Tomography ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Time Course ◽  
Single Photon ◽  
Photon Emission ◽  
Emission Computed Tomography ◽  
Ischemic Penumbra ◽  
Critical Ischemia ◽  
Irreversible Damage

The ischemic penumbra is defined as tissue with flow within the thresholds for maintenance of function and of morphologic integrity. Penumbra tissue has the potential for recovery and therefore is the target for interventional therapy in acute ischemic stroke. The identification of the penumbra necessitates measuring flow reduced less than the functional threshold and differentiating between morphologic integrity and damage. This can be achieved by multitracer positron emission tomography (PET) and perfusion-weighted (PW) and diffusion-weighted magnetic resonance imaging (DW-MRI) in experimental models, in which the recovery of critically perfused tissue or its conversion to infarction was documented in repeat studies. Neuroimaging modalities applied in patients with acute ischemic stroke—multitracer PET, PW-and DW-MRI, single photon emission computed tomography (SPECT), perfusion, and Xe-enhanced computed tomography (CT)—often cannot reliably identify penumbra tissue: multitracer studies for the assessment of flow and irreversible metabolic damage usually cannot be performed in the clinical setting; CT and MRI do not reliably detect irreversible damage in the first hours after stroke, and even DW-MRI may be misleading in some cases; determinations of perfusion alone yield a poor estimate of the state of the tissue as long as the time course of changes is not known in individual cases. Therefore, the range of flow values in ischemic tissue found later, either within or outside the infarct, was rather broad. New tracers—for example, receptor ligands or hypoxia markers—might improve the identification of penumbra tissue in the future. Despite these methodologic limitations, the validity of the concept of the penumbra was proven in several therapeutic studies in which thrombolytic treatment reversed critical ischemia and decreased the volume of final infarcts. Such neuroimaging findings might serve as surrogate targets in the selection of other therapeutic strategies for large clinical trials.

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 AP-1 (Activated Protein-1) Transcription Factor JunD Regulates Ischemia/Reperfusion Brain Damage via IL-1β (Interleukin-1β)

Stroke ◽  
2019 ◽  
Vol 50 (2) ◽  
pp. 469-477 ◽  
Author(s):  
Candela Diaz-Cañestro ◽  
Martin F. Reiner ◽  
Nicole R. Bonetti ◽  
Luca Liberale ◽  
Mario Merlini ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Acute Ischemic Stroke ◽  
Peripheral Blood ◽  
Ischemia Reperfusion ◽  
Interleukin 1Β ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes

Background and Purpose— Inflammation is a major pathogenic component of ischemia/reperfusion brain injury, and as such, interventions aimed at inhibiting inflammatory mediators promise to be effective strategies in stroke therapy. JunD—a member of the AP-1 (activated protein-1) family of transcription factors—was recently shown to regulate inflammation by targeting IL (interleukin)-1β synthesis and macrophage activation. The purpose of the present study was to assess the role of JunD in ischemia/reperfusion-induced brain injury. Methods— WT (wild type) mice randomly treated with either JunD or scramble (control) siRNA were subjected to 45 minutes of transient middle cerebral artery occlusion followed by 24 hours of reperfusion. Stroke size, neurological deficit, plasma/brain cytokines, and oxidative stress determined by 4-hydroxynonenal immunofluorescence staining were evaluated 24 hours after reperfusion. Additionally, the role of IL-1β was investigated by treating JunD siRNA mice with an anti–IL-1β monoclonal antibody on reperfusion. Finally, JunD expression was assessed in peripheral blood monocytes isolated from patients with acute ischemic stroke. Results— In vivo JunD knockdown resulted in increased stroke size, reduced neurological function, and increased systemic inflammation, as confirmed by higher neutrophil count and lymphopenia. Brain tissue IL-1β levels were augmented in JunD siRNA mice as compared with scramble siRNA, whereas no difference was detected in IL-6, TNF-α (tumor necrosis factor-α), and 4-hydroxynonenal levels. The deleterious effects of silencing of JunD were rescued by treating mice with an anti–IL-1β antibody. In addition, JunD expression was decreased in peripheral blood monocytes of patients with acute ischemic stroke at 6 and 24 hours after onset of stroke symptoms compared with sex- and age-matched healthy controls. Conclusions— JunD blunts ischemia/reperfusion-induced brain injury via suppression of IL-1β.

scholarly journals Dynamic capillary stalls in reperfused ischemic penumbra contribute to injury: A hyperacute role for neutrophils in persistent traffic jams

2020 ◽  
pp. 0271678X2091417 ◽  
Author(s):  
Şefik E Erdener ◽  
Jianbo Tang ◽  
Kıvılcım Kılıç ◽  
Dmitry Postnov ◽  
John T Giblin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cellular Damage ◽  
Ischemic Penumbra ◽  
Dynamic Flow ◽  
Traffic Jams ◽  
Activated Neutrophils ◽  
Resolution Imaging ◽  
Spatio Temporal ◽  
Capillary Circulation

Ever since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in salvageable penumbra after reperfusion. These stalls, which are different from permanent cellular plugs of no-reflow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling slowly through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments under reperfused conditions. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. Decreased number and duration of stalls were associated with improvement in penumbral blood flow within 2–24 h after reperfusion along with increased capillary oxygenation, decreased cellular damage and improved functional outcome. Thereby, dynamic microcirculatory stall phenomenon can be a contributing factor to ongoing penumbral injury and is a potential hyperacute mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke.

Optimal thresholds for ischemic penumbra predicted by computed tomography perfusion in patients with acute ischemic stroke treated with mechanical thrombectomy

2017 ◽  
Vol 10 (3) ◽  
pp. 279-284 ◽  
Author(s):  
Katsuharu Kameda ◽  
Junji Uno ◽  
Ryosuke Otsuji ◽  
Nice Ren ◽  
Shintaro Nagaoka ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Cerebral Blood Volume ◽  
Mechanical Thrombectomy ◽  
Ct Perfusion ◽  
Characteristic Curve ◽  
Mean Transit Time ◽  
Area Under The Curve ◽  
Ischemic Penumbra ◽  
Optimal Thresholds

Background and purposeOptimal thresholds for ischemic penumbra detected by CT perfusion (CTP) in patients with acute ischemic stroke (AIS) have not been elucidated. In this study we investigated optimal thresholds for salvageable ischemic penumbra and the risk of hemorrhagic transformation (HT).MethodsA total of 156 consecutive patients with AIS treated with mechanical thrombectomy (MT) at our hospital were enrolled. Absolute (a) and relative (r) CTP parameters including cerebral blood flow (aCBF and rCBF), cerebral blood volume (aCBV and rCBV), and mean transit time (aMTT and rMTT) were evaluated for their value in detecting ischemic penumbra in each of seven arbitrary regions of interest defined by the major supplying blood vessel. Optimal thresholds were calculated by performing receiver operating characteristic curve analysis in 47 patients who achieved Thrombolysis In Cerebral Infarction (TICI) grade 3 recanalization. The risk of HT after MT was evaluated in 101 patients who achieved TICI grade 2b–3 recanalization.ResultsAbsolute CTP parameters for distinguishing ischemic penumbra from ischemic core were as follows: aCBF, 27.8 mL/100 g/min (area under the curve 0.82); aCBV, 2.1 mL/100 g (0.75); and aMTT, 7.30 s (0.70). Relative CTP parameters were as follows: rCBF, 0.62 (0.81); rCBV, 0.83 (0.87); and rMTT, 1.61 (0.73). CBF was significantly lower in areas of HT than in areas of infarction (aCBF, p<0.01; rCBF, p<0.001).ConclusionsCTP may be able to predict treatable ischemic penumbra and the risk of HT after MT in patients with AIS.

scholarly journals Neutrophil-mediated dynamic capillary stalls in ischemic penumbra: persistent traffic jams after reperfusion contribute to injury

2019 ◽  
Author(s):  
Şefik Evren Erdener ◽  
Jianbo Tang ◽  
Kıvılcım Kılıç ◽  
Dmitry Postnov ◽  
John Thomas Giblin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Capillary Flow ◽  
Tissue Injury ◽  
Cellular Damage ◽  
Ischemic Penumbra ◽  
Traffic Jams ◽  
Activated Neutrophils ◽  
Spatio Temporal ◽  
Capillary Circulation

AbstractEver since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in the salvageable penumbra after recanalization. These stalls, which are distinct from permanent cellular plugs that can lead to no-flow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments, within 3 hours after stroke onset. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. By decreasing the number and duration of stalls, we were able to improve the blood flow in the penumbra within 2-24 hours after reperfusion, increase capillary oxygenation, decrease cellular damage and improve functional outcome. Thereby the dynamic microcirculatory stall phenomenon contributes to the ongoing penumbral injury and is a potential hyperacute stage mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke.SignificanceThis work provides in vivo evidence that, even in perfused capillaries, abnormal capillary flow patterns in the form of dynamic stalls can contribute to ongoing tissue injury in the salvageable penumbra in very early hours of cerebral ischemia. These events resembling micro traffic jams in a complex road network, are mediated by passage of neutrophils through the microcirculation and persist despite recanalization of the occluded artery.

scholarly journals Infarct Progression in the Early and Late Phases of Acute Ischemic Stroke

Neurology ◽  
2021 ◽  
Vol 97 (20 Supplement 2) ◽  
pp. S60-S67
Author(s):  
Hamidreza Saber ◽  
David S. Liebeskind
Keyword(s):  
At Risk ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Late Phase ◽  
Functional Independence ◽  
Irreversible Damage ◽  
Ischemic Tissue ◽  
Underlying Pathophysiology ◽  
Core Infarct ◽  
Brain Energy

Purpose of ReviewTo explore factors associated with infarct progression in the early and late phase of acute ischemic stroke in patients undergoing endovascular therapy.Recent FindingsFollowing ischemic stroke, brain injury can progress at a variable rate, at the expense of “penumbral tissue,” which is the ischemic tissue at risk of infarction. Despite dramatic advances in endovascular stroke therapies with early revascularization in more than 80% of cases, nearly half of patients do not achieve functional independence despite successful recanalization. This is largely attributed to the irreversible damage that is already extensive at the time of revascularization.SummaryThe underlying pathophysiology and determinants of the core infarct progression are complex and multifactorial, depending on a balance between brain energy consumption and collateral perfusion supply. It is crucial to develop creative and individualized theranostics to predict infarct progression and to “freeze” the tissue at risk prior to recanalization.

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.

Abstract 712: Screening of Thrombolytic Agents in vivo Using a Novel Zebrafish Model of Ischemic Stroke Induced by Photochemical Thrombosis

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Jia-Wen Hsu ◽  
I-Ju Lee ◽  
Wei-Tien Chang ◽  
Yung-Jen Chuang ◽  
Ian Liau
Keyword(s):  
Blood Flow ◽  
Ischemic Stroke ◽  
Blood Vessel ◽  
Acute Ischemic Stroke ◽  
Zebrafish Model ◽  
Thrombolytic Activity ◽  
Larval Zebrafish ◽  
Thrombolytic Agents ◽  
Partially Occluded

Background: Timely thrombolytic therapy for acute ischemic stroke is important for improving neurological prognosis. Screening of thrombolytic agents on contemporary animal models of focal ischemic stroke is generally difficult as they require sophisticated surgical procedures such as induction of cerebral artery occlusion through mechanical ligation. Herein we seek to develop a novel zebrafish (Danio rerio) model of acute ischemic stroke for screening of thrombolytic drugs. Methods: All experiments were performed on a modified confocal optical microscope, which allows the induction of thrombosis at a selected blood vessel of larval zebrafish and the imaging of thrombotic and thrombolytic processes in real time. To initiate photochemical thrombosis, a 532-nm laser was focused at a blood vessel of a larva (4 dpf) that had been injected with a photosensitizer (rose bengal). To test the thrombolytic activity of tPA, we injected tPA to the blood vessel of a larval with a thrombus that partially occluded the blood flow. Results: Through photochemical means, we induced endothelial injury at selected blood vessel which subsequently triggered thrombosis. We show that an occlusion at the 1st branch of central artery drastically diminished the hemodynamics and cardiac function of larval zebrafish and impaired their capability to maintain balance during swimming whereas that at the basilar artery resulted in a high death rate. Immunofluorescent imaging shows that the photochemically induced thrombus comprised fibrins and platelets. After the injection of tPA to a larval with a partially occluded blood vessel, the fibrin mesh on the thrombus appeared sparse and limp which eventually led to the restoration of blood flow. Conclusions: Our zebrafish model of ischemic stroke is convenient to adapt and is highly reproducible. This model can potentially become an effective platform that benefits the screening of thrombolytic agents and the optimization of their dose.

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