Acute treatment by a PPAR-α agonist decreases cerebral infarct volume and prevents post-ischemic endothelium and Kir 2.1 impairment

Background: Transient Ischemia/Reperfusion (I/R) is the main reason for brain injury and results in disruption of the Blood-Brain Barrier (BBB). It had been reported that BBB injury is one of the main risk factors for early death in patients with cerebral ischemia. Numerous investigations focus on the study of BBB injury which have been carried out. Objective: The objective of this study was to investigate the treatment function of the activation of the Hippo/Yes-Associated Protein (YAP) signaling pathway by combined Ischemic Preconditioning (IPC) and resveratrol (RES) before brain Ischemia/Reperfusion (BI/R) improves Blood-Brain Barrier (BBB) disruption in rats. Methods: Sprague-Dawley (SD) rats were pretreated with 20 mg/kg RES and IPC and then subjected to 2 h of ischemia and 22 h of reperfusion. The cerebral tissues were collected; the cerebral infarct volume was determined; the Evans Blue (EB) level, the brain Water Content (BWC), and apoptosis were assessed; and the expressions of YAP and TAZ were investigated in cerebral tissues. Results: Both IPC and RES preconditioning reduced the cerebral infarct size, improved BBB permeability, lessened apoptosis, and upregulated expressions of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) compared to the Ischemia/Reperfusion (I/R) group, while combined IPC and RES significantly enhanced this action. Conclusion: combined ischemic preconditioning and resveratrol improved blood-brain barrier breakdown via Hippo/YAP/TAZ signaling pathway.

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Abstract W P218: Interleukin 21 receptor: A Major Modulator of Infarct Volume

Stroke ◽

10.1161/str.45.suppl_1.wp218 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Han Kyu Lee ◽

Sehoon Keum ◽

Donald C Lo ◽

Douglas A Marchuk

Keyword(s):

Infarct Volume ◽

Brain Slices ◽

Oxygen Deprivation ◽

Cerebral Infarct ◽

Adult Brain ◽

Chromosome 7 ◽

Mouse Strains ◽

Circulatory Effects ◽

A Genome ◽

Interleukin 21

Using the permanent middle cerebral artery occlusion (MCAO) model of stroke, we have demonstrated that different inbred mouse strains show profound differences in infarct volume, indicating that infarction is under strong genetic control. To identify natural genetic determinants modulating infarction, we employed quantitative trait locus (QTL) linkage analysis and a genome-wide association study of cerebral infarct volume. We identified a locus on distal chromosome 7 that contributes over 50% of the variation in infarct volume, as well as other loci of smaller effect. Using interval-specific ancestral haplotype analysis, we fine-mapped the chromosome 7 locus to only 12 candidate genes. To identify the gene(s) underlying this locus, we determined the strain-specific transcript levels of all 12 genes in relevant tissues that included P1 and adult brain cortex, and embryonic macrophages, the latter due to their importance in the development of the cerebrovascular system. One gene, interleukin 21 receptor (Il21r), showed a 7-fold expression difference between strains and harbors a coding SNP difference that segregates with infarct volume. To determine whether Il21r is a major modulator of infarction, we examined Il21r in mice for their cerebrovascular anatomy as well as the cerebral infarct volume after MCAO. While Il21r-/- mice show a moderate reduction in collateral vessel connections compared to wild-type littermate mice cerebral infarct volume in Il21r-/- mice is increased 3-fold. This suggests that Il21r has effects on both cerebrovascular anatomy and innate neuroprotection. To examine the latter, we performed an ex vivo study of brain slices under in vitro oxygen deprivation. In this system devoid of any potential circulatory effects, but retaining appropriate tissue architecture, Il21r-/- brain slices showed an increase in oxygen-deprivation induced cell death, showing that Il21r is also involved in cerebrovascular-independent neuroprotection. Biochemical studies of the brain slices show that Il21R regulates ischemia-induced apoptosis. The identification of Il21R as a cerebrovascular-independent modulator of infarct volume provides a fundamental advance in the understanding of genetic modulation of ischemic stroke.

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GPVI-Fc-PEG improves cerebral infarct volume and cerebral thrombosis in mouse model with cerebral thrombosis

Molecular Medicine Reports ◽

10.3892/mmr.2017.7556 ◽

2017 ◽

Vol 16 (5) ◽

pp. 7561-7568 ◽

Cited By ~ 1

Author(s):

Yimae Wufuer ◽

Xuefeng Shan ◽

Magaoweiya Sailike ◽

Kamile Adilaimu ◽

Songfeng Ma ◽

...

Keyword(s):

Mouse Model ◽

Infarct Volume ◽

Cerebral Infarct ◽

Cerebral Thrombosis

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KADAR FIBRIN MONOMER DAN UKURAN INFARK DI STROK ISKEMIK AKUT

INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY ◽

10.24293/ijcpml.v20i3.470 ◽

2016 ◽

Vol 20 (3) ◽

pp. 171

Author(s):

Ani Kartini ◽

Mansyur Arif ◽

Hardjoeno Hardjoeno

Keyword(s):

Ischemic Stroke ◽

Infarct Size ◽

Acute Ischemic Stroke ◽

Thrombus Formation ◽

Infarct Volume ◽

Cross Sectional Study ◽

Cerebral Infarct ◽

Cross Sectional ◽

Fibrin Monomer ◽

Significant Difference

Coagulation activation and thrombosis frequently exist in ischemic stroke, thrombus formation can be detected early by the presence of fibrin monomer. The purpose of this study was to know the correlation of fibrin monomer level with cerebral infarct size in acute ischemic stroke patients. This was a cross sectional study with a total of 39 samples. The fibrin monomer level was determined by immunoturbidimetry method using STA-Compact and the measurement of the infarct size was done by CT scan of the head using Broderick formula. The results of this study showed that the median level of fibrin monomer in acute ischemic stroke with nonlacunar infarct type and lacunar infarct type were 14.46 μg/mL and 4.29 μg/mL, respectively. Mann-Whitney test showed there was a significant difference of fibrin monomer levels between nonlacunar infarct type and the lacunar type, p=0.000. The cut-off point analysis result of the fibrin monomer level was 5.96 μg/mL with a sensitivity of 88.9% and specificity of 76.4%, respectively. Spearman correlation test showed that fibrin monomer level was positively correlated with cerebral infarct volume in acute ischemic stroke (r=0.56, p=0.000). Based on this study, it can be concluded that fibrin monomer level can be used as a marker to predict the type of cerebral infarct and volume of acute ischemic stroke as well.

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Early Effects of Acid-Base Management during Hypothermia on Cerebral Infarct Volume, Edema, and Cerebral Blood Flow in Acute Focal Cerebral Ischemia in Rats

Anesthesiology ◽

10.1097/00000542-200210000-00018 ◽

2002 ◽

Vol 97 (4) ◽

pp. 868-874 ◽

Cited By ~ 26

Author(s):

Rainer Kollmar ◽

Thomas Frietsch ◽

Dimitrios Georgiadis ◽

Wolf-Rüdiger Schäbitz ◽

Klaus F. Waschke ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Cerebral Edema ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Cerebral Infarct ◽

Moderate Hypothermia ◽

Acid Base ◽

Base Management ◽

Ph Stat

Background Although the frequency for the use of moderate hypothermia in acute ischemic stroke is increasing, the optimal acid-base management during hypothermia remains unclear. This study investigates the effect of pH- and alpha-stat acid-base management on cerebral blood flow (CBF), infarct volume, and cerebral edema in a model of transient focal cerebral ischemia in rats. Methods Twenty Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h during normothermic conditions followed by 5 h of reperfusion during hypothermia (33 degrees C). Animals were artificially ventilated with either alpha- (n = 10) or pH-stat management (n = 10). CBF was analyzed 7 h after induction of MCAO by iodo[(14)C]antipyrine autoradiography. Cerebral infarct volume and cerebral edema were measured by high-contrast silver infarct staining (SIS). Results Compared with the alpha-stat regimen, pH-stat management reduced cerebral infarct volume (98.3 +/- 33.2 mm(3) vs. 53.6 +/- 21.6 mm(3); P > or = 0.05 mean +/- SD) and cerebral edema (10.6 +/- 4.0% vs. 3.1 +/- 2.4%; P > or = 0.05). Global CBF during pH-stat management exceeded that of alpha-stat animals (69.5 +/- 12.3 ml x 100 g(-1) x min(-1) vs. 54.7 +/- 13.3 ml x 100 g(-1) x min; P > or = 0.05). The regional CBF of the ischemic hemisphere was 62.1 +/- 11.2 ml x 100 g(-1) x min(-1) in the pH-stat group versus 48.2 +/- 7.2 ml x 100 g(-1) x min(-1) in the alpha-stat group ( P> or = 0.05). Conclusions In the very early reperfusion period (5 h), pH-stat management significantly decreases cerebral infarct volume and edema as compared with alpha-stat during moderate hypothermia, probably by increasing CBF.

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Abstract TP111: Activation of the Brain Renin-Angiotensin System by Translational Approaches Following Stroke Onset Is Neuroprotective in a Rat Model of Ischemic Stroke

Stroke ◽

10.1161/str.44.suppl_1.atp111 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Douglas M Bennion ◽

Lauren Donnangelo ◽

David Pioquinto ◽

Robert Regenhardt ◽

Mohan K Raizada ◽

...

Keyword(s):

Ischemic Stroke ◽

Infarct Volume ◽

Renin Angiotensin System ◽

Cerebral Infarct ◽

Intraventricular Administration ◽

Angiotensin System ◽

Renin Angiotensin ◽

Post Stroke ◽

Neurologic Deficits ◽

The Brain

Background: Toward discovering novel stroke therapies, recent research has shown that activation of the newly-discovered angiotensin converting enzyme 2/angiotensin-(1-7)/mas (ACE2/Ang-(1-7)/Mas) pathway, a counter-regulatory axis of the brain renin-angiotensin system, is neuroprotective in ischemic stroke in rats. Specifically, intraventricular administration of the novel ACE2 activator diminazine aceturate (DIZE) before and during an ischemic stroke decreases cerebral infarct and neurologic deficits. Efficacy must now be demonstrated using minimally-invasive methods if this therapy is to be translated to the care of human patients. In this study, we assessed the hypothesis that systemic administration of DIZE post ischemic stroke would be neuroprotective. Methods: Adult male Sprague-Dawley rats underwent ischemic stroke by endothelin-1 induced middle cerebral artery occlusion and were randomly divided into 2 groups (n=9-10/set): 1) intraperitoneal (IP) administrations of DIZE (7.5 mg/kg) at 4, 24, and 48 h after stroke; 2) IP administrations of 0.9% saline vehicle at the same time points. At 24 and 72 h after stroke, rats underwent blinded neurologic assessments. Immediately following the 72 h tests, animals were sacrificed, cerebral infarct volumes assessed by TTC staining, and IL-1β expression in the stroke region analyzed by rt-PCR. Data are expressed as mean ± SEM with significance inferred at p<0.05. Results: Mean infarct volume was significantly decreased by IP injections of DIZE (9.4% ± 4.35) as compared to control (22.8%±3.6, p=0.039). At 24 h post stroke, neurologic deficits (Garcia Scale) were significantly improved in the DIZE treated group (16.7±0.40) versus the saline group (15.22±0.57, p=0.037). Although DIZE tended to improve neurologic deficits 72 h post stroke, this trend was not significant. Finally, DIZE treatment significantly reduced mRNA expression of IL-1β (0.43 ± 0.14) in the cerebral cortical stroke region as compared to saline treatment (1.47±0.08, p=0.001). Conclusions: Our findings suggest that targeting the ACE2/Ang-(1-7)/Mas axis post stroke can improve function, decrease inflammation, and reduce infarct volume - a significant translational step in brain renin-angiotensin system research.

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Final Cerebral Infarct Volume Is Predictable by MR Imaging at 1 Week

American Journal of Neuroradiology ◽

10.3174/ajnr.a2271 ◽

2010 ◽

Vol 32 (2) ◽

pp. 352-358 ◽

Cited By ~ 24

Author(s):

T. Tourdias ◽

P. Renou ◽

I. Sibon ◽

J. Asselineau ◽

L. Bracoud ◽

...

Keyword(s):

Mr Imaging ◽

Infarct Volume ◽

Cerebral Infarct

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Mechanisms Contributing to Cerebral Infarct Size after Stroke: Gender, Reperfusion, T Lymphocytes, and Nox2-Derived Superoxide

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2010.14 ◽

2010 ◽

Vol 30 (7) ◽

pp. 1306-1317 ◽

Cited By ~ 109

Author(s):

Vanessa H Brait ◽

Katherine A Jackman ◽

Anna K Walduck ◽

Stavros Selemidis ◽

Henry Diep ◽

...

Keyword(s):

Ischemic Stroke ◽

T Lymphocytes ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Fold Increase ◽

Cerebral Infarct ◽

Male Mice ◽

Female Mice ◽

Underlying Mechanisms ◽

Cerebral Reperfusion

Cerebral infarct volume is typically smaller in premenopausal females than in age-matched males after ischemic stroke, but the underlying mechanisms are poorly understood. In this study we provide evidence in mice that this gender difference only occurs when the ischemic brain is reperfused. The limited tissue salvage achieved by reperfusion in male mice is associated with increased expression of proinflammatory proteins, including cyclooxygenase-2 (Cox-2), Nox2, and vascular cell adhesion molecule-1 (VCAM-1), and infiltration of Nox2-containing T lymphocytes into the infarcted brain, whereas such changes are minimal in female mice after ischemia–reperfusion (I-R). Infarct volume after I-R was no greater at 72 h than at 24 h in either gender. Infarct development was Nox2 dependent in male but not in female mice, and Nox2 within the infarct was predominantly localized in T lymphocytes. Stroke resulted in an ∼15-fold increase in Nox2-dependent superoxide production by circulating, but not spleen-derived, T lymphocytes in male mice, and this was ∼sevenfold greater than in female mice. These circulating immune cells may thus represent a major and previously unrecognized source of superoxide in the acutely ischemic and reperfused brain of males (and potentially in postmenopausal females). Our findings provide novel insights into mechanisms that could be therapeutically targeted in acute ischemic stroke patients who receive thrombolysis therapy to induce cerebral reperfusion.

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