Abstract W P220: Suppression of Interleukin 33 Limits Ischemic Brain Injury and Improves Functional Outcome in Murine Stroke Model

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Atif Zafar ◽  
Mohammad M Khan ◽  
Asgar Zaheer
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Functional Outcome ◽  
Ischemia Reperfusion ◽  
Neutralizing Antibody ◽  
Neurological Deficits ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Interleukin 33 ◽  
The Brain

Background and purpose: Ischemic stroke is a leading cause of death and disability worldwide, and the treatment options are limited. Interleukin-33 (IL-33) is a newly recognized IL-1 family cytokine which signals via its ST2 receptor, and acts as a key regulator of inflammation. However, the expression of IL-33 in the brain was not well studied and its expression in ischemic stroke remains to be elucidated. In the present study, we measured IL-33 and ST2 levels and examine the correlation of IL-33 expression with brain damage and functional outcome following ischemic stroke. Methods: IL-33 expression was examined in ischemic brain hemisphere. Mice were subjected to middle cerebral artery occlusion (MCAO) for 1 hr using a filament model, followed by 23 hrs reperfusion. Briefly, mice were anesthetized with 1-1.5% isoflurane mixed with medical oxygen. Body temperature was maintained at 37°C ± 1.0 using a heating pad. At 23 hours after ischemia/reperfusion, mice were tested for neurological scores and were sacrificed for the estimation of IL-33 and ST2 expression. Expression of IL-33 and its receptor ST2 was monitored by ELISA, Western blot and immunohistochemistry. The neurobehavioral scores, infarction volumes, expression of NF-kB and proinflammatory cytokines were evaluated after ischemia/reperfusion. Results: We found significantly increased expression level of IL-33 and ST2 in the MCAO mice as compare to the saline treated control mice. Moreover, treating the MCAO mice with recombinant IL-33 increases the brain injury and worsens neurological deficits in MCAO mice as compare to control mice. Interestingly, increased ischemic brain damage and neurological deficits were largely abrogated in mice treated with IL-33 neutralizing antibody. Conclusion: These findings provide the first evidence that IL-33/ST2 signaling plays an important role in the pathogenesis of stroke. Moreover, IL-33 exacerbates inflammatory brain injury after ischemic stroke and treatment with specific IL-33 neutralizing antibody inhibited the ischemic brain injury. Therefore, blocking the IL-33 may represent an efficient therapy in stroke.

Abstract TP269: Lncrna-u90926 Aggravates Ischemic Brain Injury via Promoting Neutrophils Infiltration After Experimental Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Jian Chen ◽  
Yun Xu
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Expression Level ◽  
Neurological Deficits ◽  
Neurological Injury ◽  
Experimental Stroke ◽  
Ischemic Brain Injury ◽  
Triphenyltetrazolium Chloride ◽  
Ischemic Brain ◽  
Severity Scores

Background: Long non-coding RNAs (LncRNAs) are expressed at high levels in the brain in a variety of neuropathologic conditions, including stroke. However, the potential role of LncRNAs in ischemic stroke-associated microglial biological function and neurological injury remains largely unknown. Methods: Oxygen-glucose deprivation and transient middle cerebral artery occlusion (MCAO) in C57BL/6 mice were used as in vitro and in vivo ischemic stroke models. Microarray analysis was performed to explore the overall expression level changes of LncRNAs. Real-time polymerase chain reaction (RT-qPCR) was used to detect expression level of LncU90926 in brain, plasma and microglia. ShRNA-LncU90926 in lentivirus and microglia specific Adeno-associated virus (AAV) were used to knockdown LncU90926 in vitro and in vivo separately. Infarct volumes and neurological impairments were assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining, Neurological Severity Scores (NSS), rotarod test and grip strength respectively. Immunofluorescence staining and flow cytometry were performed to detect the number of neutrophils recruited to brain. RT-qPCR was used to detect the level of chemokines (CXCL, CCL2) and inflammatory mediators associated with neutrophils (MPO, MMP3 and TIMP1). Results: (1). LncU90926 was markedly up-regulated in the infarcted brain and plasma after MCAO. Both MCAO and OGD treatment induced remarkable up-regulation of LncU90926 in microglia. (2). LncU90926 knockdown definitely attenuated brain infarct size and neurological deficits after ischemic stroke. (3). LncU90926 knockdown in microglia reduced the number of neutrophils recruited to brain, and CXCL1 and CCL2 were down-regulated in both MCAO and OGD models. LncU90926 knockdown also induced reduction of MPO, MMP3 and TIMP1 in the infarcted brain. Conclusions: LncU90926 was up-regulated in microglia after experimental stroke, and aggravates ischemic brain injury through facilitating neutrophils infiltration via up-regulating microglial chemokine.

EDA-Containing Fibronectin Aggravates Ischemic Brain Injury In Mice

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 330-330
Author(s):  
Anil Chauhan ◽  
Mohammad M Khan ◽  
Chintan Gandhi ◽  
Neelam Chauhan ◽  
Asgar Zaheer ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Experimental Model ◽  
Vascular Injury ◽  
Laser Doppler Flowmetry ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Ischemic Brain Injury ◽  
Doppler Flowmetry ◽  
Ischemic Brain

Abstract Abstract 330 Background: Fibronectin (FN) is a dimeric glycoprotein that plays an important role in several cellular processes, such as embryogenesis, malignancy, hemostasis, wound healing and maintenance of tissue integrity. FN is a ligand for many members of the integrin family (e.g. αIIbβ3, α5β1, α4β1, α9β1, αvβ3 and αvβ5) and also binds to thrombosis-related proteins including heparin, collagen and fibrin. FN generates protein diversity as a consequence of alternative processing of a single primary transcript. Two forms of FN exist; soluble plasma FN (pFN), which lacks the alternatively-spliced Extra Domain A (EDA); and insoluble cellular FN (cFN), which contains EDA. FN containing EDA (EDA+FN) is normally absent in plasma of human and mouse but EDA+FN has been found in patients with vascular injury secondary to vasculitis, sepsis, acute major trauma or ischemic stroke. We tested the hypothesis that elevated levels of plasma EDA+FN increase brain injury in an experimental model of ischemic stroke in mice. Model and Method: We used two genetically modified mouse strains: EDA+/+ mice contain optimized spliced sites at both splicing junctions of the EDA exon and constitutively express only EDA+FN, whereas EDA-/- mice contain an EDA-null allele of the EDA exon and express only FN lacking EDA. Control EDAwt/wt mice contain the wild-type FN allele. Transient focal cerebral ischemia was induced by 60 minutes of occlusion of the right middle cerebral artery with a 7.0 siliconized filament in male mice (8-10 weeks in age). Mice were anesthetized with 1–1.5% isoflurane mixed with medical air. Body temperature was maintained at 37°C ± 1.0 using a heating pad. Laser Doppler flowmetry was used to confirm induction of ischemia and reperfusion. At 23 hours after MCAO, mice were evaluated for neurological deficits as a functional outcome and were sacrificed for quantification of infarct volume. For morphometric measurement eight 1 mm coronal sections were stained with 2% triphenyl-2, 3, 4-tetrazolium-chloride (TTC). Sections were digitalized and infarct areas were measured blindly using NIS elements. Result: In EDA+/+ mice the percentage of infarct volume (mean ± SEM: 37.25 ± 4.11, n= 12,) in the ipsilateral (ischemic) hemisphere was increased by approximately two-fold compared to EDA wt/wt mice (mean ± SEM: 22.33 ± 3.39, n=11; P< 0.05, ANOVA) or EDA-/- mice (mean ± SEM: 21.72 ± 2.94, n=9). Regional cerebral blood flow during ischemia was not different among groups as assessed by laser Doppler flowmetry. The percentage increase in infarct volume in the EDA+/+ mice correlated well with severe neurological deficits (motor-deficit assessed by a four-point neurological score scale) compared to EDA wt/wt or EDA-/- mice. Because both thrombosis and inflammation contributes to brain injury during ischemic stroke, we investigated the time to form an occlusive thrombus in ferric-chloride carotid artery injury model by intravital microscopy. EDA+/+ mice demonstrated significantly faster time to occlusion (mean ± SEM: 12.35 ± 1.51 n=12,) compared to EDAwt/wt (Mean ± SEM: 17.27 ± 1.72 min, n=13, P<0.05, ANOVA) or EDA-/- (Mean ± SEM: 15.61 ± 1.76, n=11) mice. Additionally, the inflammatory response in the ischemic region was increased by two fold in EDA+/+ mice compared to EDA wt/wt and EDA-/- mice as sensed by myeloperoxidase activity and immunohistochemical analysis of neutrophils. Conclusion: EDA-containing FN is pro-thrombotic and pro-inflammatory, and aggravates ischemic brain injury in an experimental model of stroke in mice. The presence of EDA+FN in plasma may be a risk factor for vascular injury secondary to ischemic stroke. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cell Type-Specific Mechanisms in the Pathogenesis of Ischemic Stroke: The Role of Apoptosis Signal-Regulating Kinase 1

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
So Yeong Cheon ◽  
Eun Jung Kim ◽  
Jeong Min Kim ◽  
Bon-Nyeo Koo
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Cell Types ◽  
Ischemic Brain Injury ◽  
Cell Type ◽  
Ischemic Brain ◽  
Cell Type Specific ◽  
The Brain

Stroke has become a more common disease worldwide. Despite great efforts to develop treatment, little is known about ischemic stroke. Cerebral ischemia activates multiple cascades of cell type-specific pathomechanisms. Ischemic brain injury consists of a complex series of cellular reactions in various cell types within the central nervous system (CNS) including platelets, endothelial cells, astrocytes, neutrophils, microglia/macrophages, and neurons. Diverse cellular changes after ischemic injury are likely to induce cell death and tissue damage in the brain. Since cells in the brain exhibit different functional roles at distinct time points after injury (acute/subacute/chronic phases), it is difficult to pinpoint genuine roles of cell types after brain injury. Many experimental studies have shown the association of apoptosis signal-regulating kinase 1 (ASK1) with cellular pathomechanisms after cerebral ischemia. Blockade of ASK1, by either pharmacological or genetic manipulation, leads to reduced ischemic brain injury and subsequent neuroprotective effects. In this review, we present the cell type-specific pathophysiology of the early phase of ischemic stroke, the role of ASK1 suggested by preclinical studies, and the potential use of ASK suppression, either by pharmacologic or genetic suppression, as a promising therapeutic option for ischemic stroke recovery.

scholarly journals Influence of exercise training on ischemic brain injury in type 1 diabetic rats

2012 ◽  
Vol 113 (7) ◽  
pp. 1121-1127 ◽  
Author(s):  
Denise M. Arrick ◽  
Hong Sun ◽  
William G. Mayhan
Keyword(s):  
Brain Injury ◽  
Exercise Training ◽  
Vascular Function ◽  
Ischemia Reperfusion ◽  
Diabetic Rats ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Cerebrovascular Function ◽  
Pial Arterioles

While exercise training (ExT) appears to influence cerebrovascular function during type 1 diabetes (T1D), it is not clear whether this beneficial effect extends to protecting the brain from ischemia-induced brain injury. Thus our goal was to examine whether modest ExT could influence transient focal ischemia-induced brain injury along with nitric oxide synthase (NOS)-dependent dilation of cerebral (pial) arterioles during T1D. Sprague-Dawley rats were divided into four groups: nondiabetic sedentary, nondiabetic ExT, diabetic (streptozotocin; 50 mg/kg ip) sedentary, and diabetic ExT. In the first series of studies, we measured infarct volume in all groups of rats following right MCA occlusion for 2 h, followed by 24 h of reperfusion. In a second series of studies, a craniotomy was performed over the parietal cortex, and we measured responses of pial arterioles to an endothelial NOS (eNOS)-dependent, a neuronal NOS (nNOS)-dependent, and a NOS-independent agonist in all groups of rats. We found that sedentary diabetic rats had significantly larger total, cortical, and subcortical infarct volumes following ischemia-reperfusion than sedentary nondiabetic, nondiabetic ExT, and diabetic ExT rats. Infarct volumes were similar in sedentary nondiabetic, ExT nondiabetic, and ExT diabetic rats. In contrast, ExT did not alter infarct size in nondiabetic compared with sedentary nondiabetic rats. In addition, ExT diabetic rats had impaired eNOS- and nNOS-dependent, but not NOS-independent, vasodilation that was restored by ExT. Thus ExT of T1D rats lessened ischemic brain injury following middle cerebral artery occlusion and restored impaired eNOS- and nNOS-dependent vascular function. Since the incidence of ischemic stroke is increased during T1D, we suggest that our finding are significant in that modest ExT may be a viable preventative therapeutic approach to lessen ischemia-induced brain injury that may occur in T1D subjects.

Chemokines and their receptors in the brain: Pathophysiological roles in ischemic brain injury

Life Sciences ◽  
2003 ◽  
Vol 74 (2-3) ◽  
pp. 321-327 ◽  
Author(s):  
Masabumi Minami ◽  
Masamichi Satoh
Keyword(s):  
Brain Injury ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
The Brain

Abstract T MP18: In Vivo Expansion of Regulatory T cells with Interleukin-2/Interleukin-2-antibody Complex Protects against Transient Ischemic Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Haiyue Zhang ◽  
Peiying Li ◽  
Yanqin Gao ◽  
Jun Chen ◽  
Xiaoming Hu
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Brain Injury ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Treg Population ◽  
Antibody Complex

Background and Purpose: Our previous work documents the transfer of regulatory T cells (Tregs) in rodent models of ischemic stroke protects acute ischemic brain injury by regulating poststroke inflammatory response and thereby ameliorating BBB disruption. However, the low number of Tregs restricts the clinical feasibility of Treg transfer. Recently, in vivo expansion of Tregs with IL-2/IL-2-antibody complex (IL-2/IL-2Ab) was validated protective in autoimmune diseases model,renal ischemia reperfusion model and atherosclerosis. Here we investigate the beneficial effect of IL-2/IL-2Ab on ischemic stroke and decipher the underlying mechanisms. Methods: IL-2/IL-2Ab or isotype IgG was ip injected into C57/BL6 mice for 3 consecutive days. The mice are then subjected to 60-minute middle cerebral artery occlusion (MCAO) or sham operation. Brain infarction, inflammation and neurological performance was assessed up to 7 days after reperfusion. Results: Flow cytometry analysis reveals a marked increase of CD4+CD25+Foxp3+ Tregs in the blood, lymph nodes and spleens collected from IL-2/IL-2Ab-treated mice as compared to those from isotype-treated controls. Such Treg elevation could be observed since 3 days after IL-2/IL-2Ab injection and lasts until 7 days after MCAO. Immunochemistry staining confirms the increased number of Foxp3+ cells in the spleen at 3 days after MCAO in IL-2/IL-2Ab-treated mice. IL-2/IL-2Ab promotes function recovery up to 7 days after stroke, as revealed by significantly improved performance in corner test (n=6-9, ***p<0.001), rotarod test (n=8, **p<0.01), cylinder test (n=8, **p<0.01) and adhesive removal test (n=3, *p<0.05). Quantification of TTC staining and microtubule-associated protein (MAP2) staining shows reductions in brain infarct volume at 3 days (n=5-9,*p<0.05) and 7 days (n=7-9,*p<0.01), respectively, after MCAO. Meanwhile, we observed reduced infiltration of peripheral immune cells (CD3+ T cells, MPO+ neutrophils and F4/80+ macrophages) into the ischemic brain. Conclusions: Our finding suggests that IL-2/IL-2Ab treatment is a novel and clinical feasible immune therapy to expand Treg population in vivo, reduce post-stroke inflammatory responses and protect against ischemic brain injury.

Intracerebral Antioxidant Ability of Neonatal Rats After Acute Hypoxic–Ischemic Brain Injury Estimated Using the Brain Homogenate-ESR Method

2015 ◽  
Vol 46 (10) ◽  
pp. 1079-1088
Author(s):  
Akira Nakajima ◽  
Li Yang ◽  
Emiko Matsuda ◽  
Ayako Nagano ◽  
Hiroshi Sameshima ◽  
...  
Keyword(s):  
Brain Injury ◽  
Brain Homogenate ◽  
Ischemic Brain Injury ◽  
Antioxidant Ability ◽  
Neonatal Rats ◽  
Ischemic Brain ◽  
Hypoxic Ischemic Brain Injury ◽  
The Brain

scholarly journals HDAC9 Silencing Exerts Neuroprotection Against Ischemic Brain Injury via miR-20a-Dependent Downregulation of NeuroD1

2021 ◽  
Vol 14 ◽  
Author(s):  
Liangjun Zhong ◽  
Jinxiang Yan ◽  
Haitao Li ◽  
Lei Meng
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Neuronal Apoptosis ◽  
Inflammatory Factors ◽  
Cerebral Stroke ◽  
Inflammatory Factor ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Factor Release

Cerebral stroke is an acute cerebrovascular disease that is a leading cause of death and disability worldwide. Stroke includes ischemic stroke and hemorrhagic strokes, of which the incidence of ischemic stroke accounts for 60–70% of the total number of strokes. Existing preclinical evidence suggests that inhibitors of histone deacetylases (HDACs) are a promising therapeutic intervention for stroke. In this study, the purpose was to investigate the possible effect of HDAC9 on ischemic brain injury, with the underlying mechanism related to microRNA-20a (miR-20a)/neurogenic differentiation 1 (NeuroD1) explored. The expression of HDAC9 was first detected in the constructed middle cerebral artery occlusion (MCAO)-provoked mouse model and oxygen-glucose deprivation (OGD)-induced cell model. Next, primary neuronal apoptosis, expression of apoptosis-related factors (Bax, cleaved caspase3 and bcl-2), LDH leakage rate, as well as the release of inflammatory factors (TNF-α, IL-1β, and IL-6) were evaluated by assays of TUNEL, Western blot, and ELISA. The relationships among HDAC9, miR-20a, and NeuroD1 were validated by in silico analysis and ChIP assay. HDAC9 was highly-expressed in MCAO mice and OGD-stimulated cells. Silencing of HDAC9 inhibited neuronal apoptosis and inflammatory factor release in vitro. HDAC9 downregulated miR-20a by enriching in its promoter region, while silencing of HDCA9 promoted miR-20a expression. miR-20a targeted Neurod1 and down-regulated its expression. Silencing of HDAC9 diminished OGD-induced neuronal apoptosis and inflammatory factor release in vitro as well as ischemic brain injury in vivo by regulating the miR-20a/NeuroD1 signaling. Overall, our study revealed that HDAC9 silencing could retard ischemic brain injury through the miR-20a/Neurod1 signaling.

scholarly journals The Many Faces of Post-Ischemic Tau Protein in Brain Neurodegeneration of the Alzheimer’s Disease Type

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2213
Author(s):  
Ryszard Pluta ◽  
Stanisław J. Czuczwar ◽  
Sławomir Januszewski ◽  
Mirosław Jabłoński
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Tau Protein ◽  
Ischemia Reperfusion ◽  
Disease Type ◽  
Dependent Manner ◽  
Ischemic Brain ◽  
The Brain

Recent data suggest that post-ischemic brain neurodegeneration in humans and animals is associated with the modified tau protein in a manner typical of Alzheimer’s disease neuropathology. Pathological changes in the tau protein, at the gene and protein level due to cerebral ischemia, can lead to the development of Alzheimer’s disease-type neuropathology and dementia. Some studies have shown increased tau protein staining and gene expression in neurons following ischemia-reperfusion brain injury. Recent studies have found the tau protein to be associated with oxidative stress, apoptosis, autophagy, excitotoxicity, neuroinflammation, blood-brain barrier permeability, mitochondrial dysfunction, and impaired neuronal function. In this review, we discuss the interrelationship of these phenomena with post-ischemic changes in the tau protein in the brain. The tau protein may be at the intersection of many pathological mechanisms due to severe neuropathological changes in the brain following ischemia. The data indicate that an episode of cerebral ischemia activates the damage and death of neurons in the hippocampus in a tau protein-dependent manner, thus determining a novel and important mechanism for the survival and/or death of neuronal cells following ischemia. In this review, we update our understanding of proteomic and genomic changes in the tau protein in post-ischemic brain injury and present the relationship between the modified tau protein and post-ischemic neuropathology and present a positive correlation between the modified tau protein and a post-ischemic neuropathology that has characteristics of Alzheimer’s disease-type neurodegeneration.

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