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

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.

Download Full-text

Abstract WP258: ZBTB7C Is Associated With Severity Of Infarction In Cerebral Ischemia

Stroke ◽

10.1161/str.44.suppl_1.awp258 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Rose Du ◽

Jing Zhou ◽

Svetlana Lorenzano ◽

Nareerat Charoenvimolphan ◽

Baogang Qian ◽

...

Keyword(s):

Cerebral Ischemia ◽

Cerebral Infarction ◽

Candidate Genes ◽

Complex Disease ◽

Mixed Model ◽

Genetic Relatedness ◽

Infarct Volume ◽

Mouse Strains ◽

Genome Wide ◽

A Genome

Background Stroke is a complex disease that is affected by multiple genetic and environmental factors. We utilize the variability in inbred mouse strains to evaluate the genetic basis of susceptibility to cerebral infarction. Methods To identify candidate genes that contribute to this variability in susceptibility, we performed a strain survey on 33 inbred strains of mice using a permanent middle cerebral artery occlusion model. Variability in vascular anatomy was determined by examining the circle of Willis in 22 strains of mice. Infarct volume was obtained and a genome-wide association mapping was performed on 118,019 SNPs using efficient mixed-model association (EMMA) to account for population structure and genetic relatedness in inbred mice. Candidate genes from mice were validated in 34 patients with M1 occlusions from the Genes Associated with Stroke Risk and Outcomes Study (GASROS) and the STOP Stroke Study Results Two SNPs reached genome-wide significance (rs32249495 p=2.08x10-7 and rs3694965 p=2.17x10-7) and two were suggestive (rs31924033 5.61x10-6 and rs3677406 9.46x10-6). Thirty-eight genes were identified to be within 500kb of these four SNPs, corresponding to twenty-four orthologous human genes. SNPs associated with the human orthologs were validated in patients with M1 occlusions. Of these, one SNP (rs1944586, p=1.06x10-4) corresponding to the ZBTB7C gene was significant after adjusting for multiple testing. In vitro analysis demonstrated upregulation of ZBTB7C expression in endothelial cells under hypoxic conditions. Conclusion ZBTB7C may be part of a novel genetic pathway that modulates the severity of cerebral infarction and may serve as a new target for therapeutic intervention in cerebral ischemia.

Download Full-text

Identification of novel neuroprotective loci modulating ischemic stroke volume in a cross between wild-derived inbred mouse strains

10.1101/591669 ◽

2019 ◽

Author(s):

Han Kyu Lee ◽

Samuel J. Widmayer ◽

Min-Nung Huang ◽

David L. Aylor ◽

Douglas A. Marchuk

Keyword(s):

Ischemic Stroke ◽

Qtl Mapping ◽

Allelic Variation ◽

Infarct Volume ◽

Inbred Mouse ◽

Cerebral Infarct ◽

Vessel Density ◽

Mouse Strains ◽

Inbred Mouse Strains ◽

Collateral Vessel

AbstractTo identify genes involved in cerebral infarction we have employed a forward genetic approach in inbred mouse strains, using quantitative trait locus (QTL) mapping for cerebral infarct volume after middle cerebral artery occlusion. We had previously observed that infarct volume is inversely correlated with cerebral collateral vessel density in the strains. In this study, we expanded the pool of allelic variation among classical inbred mouse strains by utilizing the eight founder strains of the Collaborative Cross and found a wild-derived strain, WSB/EiJ, that breaks this general rule that collateral vessel density inversely correlates with infarct volume. WSB/EiJ and another wild-derived strain, CAST/EiJ, show the highest collateral vessel densities of any inbred strain, but infarct volume of WSB/EiJ mice is 8.7-fold larger than that of CAST/EiJ mice. QTL mapping between these strains identified four new neuroprotective loci modulating cerebral infarct volume while not affecting collateral vessel phenotypes. To identify causative variants in genes we surveyed non-synonymous coding SNPs between CAST/EiJ and WSB/EiJ and found 96 genes harboring coding SNPs predicted to be damaging and mapping within one of the four intervals. In addition, we performed RNA sequencing for brain tissue of CAST/EiJ and WSB/EiJ mice and identified 79 candidate genes mapping in one of the four intervals showing strain-specific differences in expression. The identification of the genes underlying these neuroprotective loci will provide new understanding of genetic risk factors of ischemic stroke which may provide novel targets for future therapeutic intervention of human ischemic stroke.

Download Full-text

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9591524.0056 ◽

2005 ◽

Vol 25 (1_suppl) ◽

pp. S56-S56 ◽

Cited By ~ 3

Author(s):

Thavarak Ouk ◽

Olivier Pétrault ◽

Sophie Gautier ◽

Patrick Gelé ◽

Maud Laprais ◽

...

Keyword(s):

Acute Treatment ◽

Infarct Volume ◽

Cerebral Infarct

Download Full-text

Combined Ischemic Preconditioning and Resveratrol Improved Bloodbrain Barrier Breakdown via Hippo/YAP/TAZ Signaling Pathway

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666191021144126 ◽

2020 ◽

Vol 18 (9) ◽

pp. 713-722 ◽

Cited By ~ 1

Author(s):

Ganji Hong ◽

Ying Yan ◽

Yali Zhong ◽

Jianer Chen ◽

Fei Tong ◽

...

Keyword(s):

Signaling Pathway ◽

Blood Brain Barrier ◽

Ischemic Preconditioning ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Cerebral Infarct ◽

Brain Barrier ◽

Binding Motif ◽

Blood Brain ◽

Barrier Breakdown

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.

Download Full-text

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

Download Full-text

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.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Characterization of a new double-filament model of focal cerebral ischemia in heme oxygenase-2-deficient mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00067.2003 ◽

2003 ◽

Vol 285 (1) ◽

pp. R222-R230 ◽

Cited By ~ 11

Author(s):

Shozo Goto ◽

Kenji Sampei ◽

Nabil J. Alkayed ◽

Sylvain Doré ◽

Raymond C. Koehler

Keyword(s):

At Risk ◽

Blood Flow ◽

Heme Oxygenase ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Cerebral Arteries ◽

Vascular Anatomy ◽

Mouse Strains ◽

Left Internal Carotid Artery

Variations in vascular anatomy in knockout mouse strains can influence infarct volume after middle cerebral artery (MCA) occlusion (MCAO). In wild-type (WT) and heme oxygenase-2 gene-deleted (HO2-/-) mice, infarcts were not reproducibly achieved with the standard intraluminal filament technique. The present study characterizes a double-filament model of MCAO, which was developed to produce consistent infarcts in both WT and HO2-/- mice. Diameters of most cerebral arteries were similar in WT and HO2-/- mice, although the posterior communicating artery size was variable. In halothane-anesthetized mice, two 6-0 monofilaments with blunted tips were inserted into the left internal carotid artery 6.0 and 4.5 mm past the pterygopalatine artery junction to reside distal and proximal to the origin of the MCA. The tissue “volume at risk” determined by brief dye perfusion in WT (59 ± 2% of hemisphere; ±SE) was similar to HO2-/- (62 ± 4%). The volume of tissue with cerebral blood flow <50 ml·min-1·100 g-1 was similar in WT (35 ± 9%) and HO2-/- (36 ± 11%) during MCAO and at 3 h of reperfusion (<2%). After 1 h MCAO, infarct volume was greater in HO2-/- (44 ± 6%) than WT (25 ± 3%). After increasing MCAO duration to 2 h, the difference between HO2-/- (47 ± 4%) and WT (36 ± 3%) diminished, but infarct volume remained substantially less than the volume at risk. Infusion of tin protoporphyrin IX, an HO inhibitor, during reperfusion after 1 h MCAO increased infarct volume in WT but not significantly in HO2-/- mice, although infarct volume remained less than the volume at risk. Thus greater infarct volume in HO2-/- mice is not attributable to a greater volume at risk, lower intraischemic blood flow, or poor reflow, but rather to a neuroprotective effect of HO2 activity. The double-filament model may be of use as an alternative in other murine knockout strains in which the standard filament model does not yield consistent infarcts.

Download Full-text