Abstract P798: Antimicrobial Protein Reg3a and Network Inflammatory Proteins Are Predictive of Infarct Volume and Functional Impairment in Ischemic Stroke

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Madison Sands ◽  
Jacqueline Frank ◽  
Chris McLouth ◽  
Benton Maglinger ◽  
Jill Roberts ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Ischemic Stroke ◽  
Stepwise Regression ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Infarct Volume ◽  
Antimicrobial Protein ◽  
Immune Mediated ◽  
Inflammatory Processes ◽  
Inflammatory Proteins

Introduction: Regenerating Family Member 3 Alpha (REG3A) is an antimicrobial protein secreted by the intestine and pancreas. REG3A is involved in immune-mediated inflammatory responses and helps maintain homeostasis of the gut microbiome. REG3A is elevated in patients with ischemic stroke, but its role within the gut-brain axis during stroke remains unclear. Our aim was to examine the association of plasma REG3A levels with other signaling proteins in systemic plasma during stroke, and its correlation with clinical outcomes of ischemic stroke. Methods: Intracranial and systemic plasma samples from n=25 thrombectomy subjects underwent Proximity Extension Assay via Olink Proteomics. REG3A levels and inflammatory markers were examined using bivariate regressions. Stepwise regression determined the predictability of infarct volume by REG3A. Two-tailed t-tests were used to examine the relationship between the National Institutes of Health Stroke Scale (NIHSS) and levels of REG3A. Results: Increased expression of systemic REG3A correlated with increases in infarct volume (p=.009, R=.514). Stepwise regression predicting infarct volume yielded a model including REG3A and systemic proteins such as CCL19, IL15, and IL1α (P<.001, R=.980). NIHSS scores corresponding to moderate-severe/severe strokes had increased intracranial REG3A (p<.05) and increased ratios of intracranial:systemic REG3A expression (p=.05). Conclusions: Within a network of proteins, REG3A is predictive of increased infarct volume and decreased function. Studies suggest that IL17 and IL6 induce REG3A expression. Subsequent REG3A can interact with NFkB, which transcriptionally regulates CCL19, IL1α, and IL15. In the intestine, REG3A regulates microbial synthesis of fatty acids and inflammatory processes. Fatty acids suppress cytokines such as IL6 and IL1α and are reportedly neuroprotective in stroke. Increase of systemic REG3A may reflect cellular responses to gut dysbiosis and inflammation triggered from ischemic stroke. Future studies will examine prognostic and therapeutic potential of the REG3A pathway in large vessel occlusive stroke.

Abstract P777: Statistical Modeling of Proteomic Signaling During Stroke in Patients Undergoing Thrombectomy

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Sydney Claypoole ◽  
Jacqueline Frank ◽  
Madison Sands ◽  
Christopher J McLouth ◽  
Jill Roberts ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Statistical Modeling ◽  
Internal Control ◽  
Stepwise Regression ◽  
Infarct Volume ◽  
Tissue Samples ◽  
Bivariate Regression ◽  
Inflammatory Proteins ◽  
The Relationship ◽  
Proximity Extension Assay

Introduction: The previously published Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol (clinicaltrials.gov NCT03153683) utilizes mechanical thrombectomy to obtain tissue samples for banking. Peripheral blood proximal to the clot and intracranial blood distal from the clot were isolated. Proteomic and statistical analyses revealed normalized (intracranial-systemic) CCL19 expression was a predictor of infarct volume. Statistical modeling analyses were used determine the CCL19-associated proteomic signaling network occurring during ischemic stroke relating to infarct volume. Methods: Arterial intracranial and systemic blood samples underwent analysis for inflammatory proteins using Proximity Extension Assay (PEA) via Olink (Olink Proteomics, Boston, MA). Systemic expression was used as an internal control to normalize expression in the intracranial blood. Bivariate regression was used to examine the relationship between the intracranial normalized CCL19 expression and infarct volume. A backwards stepwise regression was then used to determine a model of predictability of infarct volume by CCL19 and associated inflammatory proteins. Results: 25 subjects (>18 yrs) with a mean infarct volume of 8,172 ± 82,284 mm 3 and mean infarct time of 513 ± 246 minutes were included in this study. Their median age was 64 (24-91) and 10 (40%) were male. 16 subjects (64%) had hypertension, 15 (60%) had BMI > 25, and 6 (24%) had a previous stroke. The stepwise regression model shows normalized expression of 16 proteins correlated with an increase in infarct volume (p<0.005): CCL20, CXCL1, OSM, CD6, OSMR, TGF-alpha, TRANCE, CXCL10, LIF-R, CCL19, CDCP1, Flt3L, CCL23, CD244, TRAIL, NOTCH1. Conclusions: In our model, the expression of these proteins were consistently changed, though the directionality differed. LIF-R, NOTCH1, TRAIL, CD6, CCL23, TGF-alpha, and CCL20 were positively correlated, while the expressions of Flt3L, OSM, OSMR, TRANCE, CD244, CDCP1, CXCL1, CXCL10, and CCL19 were negatively correlated with infarct volume. This model depicts the proteomic signaling occurring during stroke in relationship to infarct volume, which reveals potential biomarkers and therapeutic targets for the early phase of ischemic stroke.

scholarly journals Phosphodiesterase 10A is a critical target for neuroprotection in a mouse model of ischemic stroke

2021 ◽  
Author(s):  
Mustafa Caglar Beker ◽  
Ahmet B. Caglayan ◽  
Serdar Altunay ◽  
Elif Ozbay ◽  
Nilay Ates ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Cyclic Monophosphate ◽  
Tnf Α ◽  
Liquid Chromatography Tandem Mass ◽  
Inflammatory Processes ◽  
Phosphodiesterase 10A ◽  
Cerebral Artery Occlusion ◽  
Blood Brain Barrier Integrity

Abstract Phosphodiesterase 10A (PDE10A) hydrolyzes adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP). It is highly expressed in the striatum. Recent evidence implied that PDE10A may be involved in the inflammatory processes following injury, such as ischemic stroke. Its role in ischemic injury was unknown. Herein, we exposed mice to 90 or 30 min middle cerebral artery occlusion, followed by the delivery of the highly selective PDE10A inhibitor TAK-063 (0.3 mg/kg or 3 mg/kg) immediately after reperfusion. Animals were sacrificed after 24 or 72 hours, respectively. Both TAK-063 doses enhanced neurological function, reduced infarct volume, increased neuronal survival, reduced brain edema, and increased blood-brain barrier integrity, alongside cerebral microcirculation improvements. Post-ischemic neuroprotection was associated with increased phosphorylation (i.e., activation) of pro-survival Akt, Erk-1/2 and GSK-3α/β, decreased phosphorylation (i.e., activation) of pro-survival mTOR, increased HIF-1α, MMP-9 and anti-apoptotic Bcl-xL abundance, and reduced pro-apoptotic Bax abundance. Interestingly, PDE10A inhibition reduced inflammatory cytokines/chemokines, including IFN-γ and TNF-α, analyzed by planar surface immunoassay. In addition, liquid chromatography-tandem mass spectrometry revealed 40 proteins were significantly altered by TAK-063. Our study established PDE10A as a target for ischemic stroke therapy.

The Protective Effects of Extra Virgin Olive Oil on Immune-mediated Inflammatory Responses

2017 ◽  
Vol 18 (1) ◽  
pp. 23-35 ◽  
Author(s):  
Rosa Casas ◽  
Ramon Estruch ◽  
Emilio Sacanella
Keyword(s):  
Fatty Acids ◽  
Olive Oil ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Virgin Olive Oil ◽  
Extra Virgin Olive Oil ◽  
Biological Properties ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Immune Mediated

Background and Objective: The increasing interest in the Mediterranean diet (MeDiet) hinges on the relevant role it plays in inflammatory diseases. Several clinical, epidemiological and experimental evidences suggest that consumption of the MeDiet reduces the incidence of certain pathologies related to oxidative stress, chronic inflammation and immune system diseases such as cancer, atherosclerosis and cardiovascular disease (CVD). These reductions can be partially attributed to extra virgin olive oil (EVOO) consumption which has been described as a key bioactive food because of its high nutritional quality and its particular composition of fatty acids, vitamins and polyphenols. Indeed, the beneficial effects of EVOO have been linked to its fatty acid composition, which is very rich in monounsaturated fatty acids (MUFA), and has moderate saturated and polyunsaturated fatty acids (PUFA). The current knowledge available on the beneficial effects of EVOO and its phenolic compounds, specifically its biological properties and antioxidant capacity against immune-mediated inflammatory responses (atherosclerosis, rheumatoid arthritis, diabetes, obesity, cancer, inflammatory bowel disease or neurodegenerative disease, among others) in addition to its potential clinical applications. Conclusion: The increasing body of studies carried out provides compelling evidence that olive polyphenols are potential candidates to combat chronic inflammatory states.

scholarly journals Phosphodiesterase 10A is a critical target for neuroprotection in a mouse model of ischemic stroke

2021 ◽  
Author(s):  
Mustafa C. Beker ◽  
Ahmet B.Caglayan ◽  
Serdar Altunay ◽  
Elif Ozbay ◽  
Nilay Ates ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Cyclic Monophosphate ◽  
Tnf Α ◽  
Liquid Chromatography Tandem Mass ◽  
Inflammatory Processes ◽  
Phosphodiesterase 10A ◽  
Cerebral Artery Occlusion ◽  
Blood Brain Barrier Integrity

Abstract Phosphodiesterase 10A (PDE10A) hydrolyzes adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP). It is highly expressed in the striatum. Recent evidence implied that PDE10A may be involved in the inflammatory processes following injury, such as ischemic stroke. Its role in ischemic injury was unknown. Herein, we exposed mice to 90 or 30 min middle cerebral artery occlusion, followed by the delivery of the highly selective PDE10A inhibitor TAK-063 (0.3 mg/kg or 3 mg/kg) immediately after reperfusion. Animals were sacrificed after 24 or 72 hours, respectively. Both TAK-063 doses enhanced neurological function, reduced infarct volume, increased neuronal survival, reduced brain edema, and increased blood-brain barrier integrity, alongside cerebral microcirculation improvements. Post-ischemic neuroprotection was associated with increased phosphorylation (i.e., activation) of pro-survival Akt, Erk-1/2 and GSK-3α/β, decreased phosphorylation (i.e., activation) of pro-survival mTOR, increased HIF-1α, MMP-9 and anti-apoptotic Bcl-xL abundance, and reduced pro-apoptotic Bax abundance. Interestingly, PDE10A inhibition reduced inflammatory cytokines/chemokines, including IFN-γ and TNF-α, analyzed by planar surface immunoassay. In addition, liquid chromatography-tandem mass spectrometry revealed 40 proteins were significantly altered by TAK-063. Our study established PDE10A as a target for ischemic stroke therapy.

scholarly journals Thiamet G mediates neuroprotection in experimental stroke by modulating microglia/macrophage polarization and inhibiting NF-κB p65 signaling

2016 ◽  
Vol 37 (8) ◽  
pp. 2938-2951 ◽  
Author(s):  
Yating He ◽  
Xiaofeng Ma ◽  
Daojing Li ◽  
Junwei Hao
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Macrophage Polarization ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Bv2 Cells ◽  
Anti Inflammatory

Inflammatory responses are accountable for secondary injury induced by acute ischemic stroke (AIS). Previous studies indicated that O-GlcNAc modification (O-GlcNAcylation) is involved in the pathology of AIS, and increase of O-GlcNAcylation by glucosamine attenuated the brain damage after ischemia/reperfusion. Inhibition of β-N-acetylglucosaminidase (OGA) with thiamet G (TMG) is an alternative option for accumulating O-GlcNAcylated proteins. In this study, we investigate the neuroprotective effect of TMG in a mouse model of experimental stroke. Our results indicate that TMG administration either before or after middle cerebral artery occlusion (MCAO) surgery dramatically reduced infarct volume compared with that in untreated controls. TMG treatment ameliorated the neurological deficits and improved clinical outcomes in neurobehavioral tests by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Additionally, TMG administration reduced the number of Iba1+ cells in MCAO mice, decreased expression of the M1 markers, and increased expression of the M2 markers in vivo. In vitro, M1 polarization of BV2 cells was inhibited by TMG treatment. Moreover, TMG decreased the expression of iNOS and COX2 mainly by suppressing NF-κB p65 signaling. These results suggest that TMG exerts a neuroprotective effect and could be useful as an anti-inflammatory agent for ischemic stroke therapy.

scholarly journals Roles of Fibroblast Growth Factors and Their Therapeutic Potential in Treatment of Ischemic Stroke

2021 ◽  
Vol 12 ◽  
Author(s):  
Confidence Dordoe ◽  
Keyang Chen ◽  
Wenting Huang ◽  
Jun Chen ◽  
Jian Hu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Growth Factors ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Fibroblast Growth Factors ◽  
Therapeutic Agents ◽  
Stroke Recovery ◽  
Fibroblast Growth ◽  
Stroke Patients ◽  
The Brain

Stroke is the leading cause of death worldwide, and its treatment remains a challenge. Complex pathological processes are involved in stroke, which causes a reduction in the supply of oxygen and energy to the brain that triggers subsequent cascade events, such as oxidative stress, inflammatory responses and apoptosis, resulting in brain injury. Stroke is a devastating disease for which there are few treatments, but physical rehabilitation can help improve stroke recovery. Although there are very few treatments for stroke patients, the discovery of fibroblast growth factors (FGFs) in mammals has led to the finding that FGFs can effectively treat stroke in animal models. As presented in this review, FGFs play essential roles by functioning as homeostatic factors and controlling cells and hormones involved in metabolism. They could be used as effective therapeutic agents for stroke. In this review, we will discuss the pharmacological actions of FGFs on multiple targets, including their ability to directly promote neuron survival, enhance angiogenesis, protect against blood-brain barrier (BBB) disruption, and regulate microglial modulation, in the treatment of ischemic stroke and their theoretical mechanisms and actions, as well as the therapeutic potential and limitations of FGFs for the clinical treatment of stroke.

scholarly journals Novel Therapeutic Effects of Leonurine On Ischemic Stroke: New Mechanisms of BBB Integrity

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Qiu-Yan Zhang ◽  
Zhi-Jun Wang ◽  
De-Miao Sun ◽  
Ying Wang ◽  
Peng Xu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Tight Junction ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Brain Diseases ◽  
Therapeutic Effects ◽  
Protective Effects

Stroke is a leading cause of morbidity and mortality globally. Leonurine (also named SCM-198), a compound extracted fromHerba leonuri, was effective on the prevention of various cardiovascular and brain diseases. The purpose of this study was to explore the possible therapeutic potential of SCM-198 against ischemia reperfusion injury and underlying mechanisms. In the in vivo transient middle cerebral artery occlusion (tMCAO) rat model, we found that treatment with SCM-198 could decrease infarct volume and improve neurological deficit by protecting against blood-brain barrier (BBB) breakdown. In the in vitro model of cell oxygen-glucose deprivation and reoxygenation (OGD/R), consistent results were obtained with decreased reactive oxygen species (ROS) production and maintained the BBB integrity. Further study demonstrated that SCM-198 increased the expression of histone deacetylase- (HDAC-) 4 which could inhibit NADPH oxidase- (NOX-) 4 and matrix metalloproteinase- (MMP-) 9 expression, resulting in the elevation of tight junction proteins, including claudin-5, occludin, and zonula occluden- (ZO-) 1. These results indicated SCM-198 protected BBB integrity by regulating the HDAC4/NOX4/MMP-9 tight junction pathway. Our findings provided novel insights into the protective effects and mechanisms of SCM-198 on ischemic stroke, indicating SCM-198 as a new class of potential drug against acute onset of ischemic stroke.

Abstract W P199: Deficiency of Glia Maturation Factor Abrogates Brain Injury and Inflammation in a Murine Model of Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Mohammad M Khan ◽  
Asgar Zaheer
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Proinflammatory Cytokines ◽  
Inflammatory Responses ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Glia Maturation Factor ◽  
Western Blots ◽  
Ischemic Brain ◽  
Maturation Factor

Background and purpose: Glia maturation factor (GMF), a brain specific protein, discovered and characterized in our laboratory, induces expression of proinflammatory cytokines/ chemokines in the central nervous system (CNS). Recently, it has been demonstrated that deficiency of GMF mitigates neuronal damage in tissue culture cell and animal models of neurodegeneration. Since, GMF expression in brain enhances inflammation; we tested the hypothesis that deficiency of GMF abrogates the inflammatory responses in experimental model of ischemic stroke. Methods: Transient focal cerebral ischemia was induced by 1 hour of occlusion of the right middle cerebral artery (MCAO) with a 7.0 monofilament in GMF-containing wild type (Wt) and GMF-deficient (GMF-KO) mice. 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 infarct volume and estimation of inflammatory responses. Immunohistochemistry and western blots were used to analyze the expression and activation of glial cells, and levels of NF-κB in ischemic brain hemisphere. Results: We found that levels of GMF significantly increased in MCAO mice compared to saline treated control mice. Next we found that GMF-KO mice exhibited significantly decreased infarct volume, and reduced neurological deficits compared to Wt mice. The decrease in infarct volume and neurological deficits in GMF-KO mice were correlated with a less activation of glia cells, downregulation of NF-κB and suppression of proinflammatory cytokines/chemokine in the ischemic region. Conclusions: In conclusion, present study provides the first evidence that deficiency of GMF reduces brain injury and inflammation after ischemic stroke and suggests that the effective suppression of endogenous GMF-function will prove to be an effective and selective strategy to slow deleterious inflammatory processes in ischemic brain injury. Keywords: Glia maturation factor; Ischemic stroke; Inflammation; Nuclear factor-κB; Cytokines

scholarly journals Endocannabinoid response in acute ischemic stroke: elevated 2-arachidonoylglycerol

2020 ◽  
Author(s):  
Marina Buciuc ◽  
Gian Marco Conte ◽  
Eugene L. Scharf
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Symptom Onset ◽  
Therapeutic Potential ◽  
Infarct Volume ◽  
Closed Head Injury ◽  
Acute Cerebral Ischemia ◽  
Ischemic Attack

ABSTRACTBackground and purposeEndocannabinoids are hypothesized to have anti-inflammatory and neuroprotective properties and hold therapeutic potential in the acute phase response mechanisms during acute cerebral ischemia and closed head injury. We set to describe the plasma levels of endocannabinoids and related ethanolamides during acute and subacute phases of cerebral ischemia.MethodsWe conducted a prospective observational study of plasma endocannabinoid levels in patients with acute ischemic stroke or transient ischemic attack. Two blood samples were collected: T1 (<12 hours from symptom onset) and T2 (>24 hours from symptom onset). N-arachidonoylethanolamine (AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were quantified by liquid chromatography mass spectrometry.ResultsTwenty-three patients met inclusion criteria. Median (interquartile range): Age – 76 years (60-81); body mass index - 25.6 (23.6-30.4); National Institutes of Health Stroke Scale score-5(3-13); infarct volume - 1.4 cm3 (0.5-8.6). Higher 2-AG levels at T1 were correlated with smaller infarct volumes (Spearman ƿ=-0.48, p=0.0206). Levels of 2-AG were elevated at T2 compared to T1 in 48% of patients (median difference - 310.3nM, 95% CI 194.1-497.3; p=0.001); AEA, PEA and OEA did not differ between T1 and T2, p>0.05. Patients with elevated 2-AG at T2 had larger infarct volumes, p=0.0178, lower frequency of embolectomy performed, p=0.0373, but no difference in neurological disability 90 days after the ischemic event compared to patients without 2-AG elevation.Conclusion2-AG increases significantly in early phases of ischemic stroke. The final mechanistic role of 2-AG in acute ischemic stroke is to be determined in further studies.

scholarly journals Phosphodiesterase 10A is a critical target for neuroprotection in a mouse model of ischemic stroke

2021 ◽  
Author(s):  
Mustafa Caglar Beker ◽  
Ahmet B. Caglayan ◽  
Serdar Altunay ◽  
Elif Ozbay ◽  
Nilay Ates ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Cyclic Monophosphate ◽  
Tnf Α ◽  
Liquid Chromatography Tandem Mass ◽  
Inflammatory Processes ◽  
Phosphodiesterase 10A ◽  
Cerebral Artery Occlusion ◽  
Blood Brain Barrier Integrity

Abstract Phosphodiesterase 10A (PDE10A) hydrolyzes adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP). It is highly expressed in the striatum. Recent evidence implied that PDE10A may be involved in the inflammatory processes following injury, such as ischemic stroke. Its role in ischemic injury was unknown. Herein, we exposed mice to 90 or 30 min middle cerebral artery occlusion, followed by the delivery of the highly selective PDE10A inhibitor TAK-063 (0.3 mg/kg or 3 mg/kg) immediately after reperfusion. Animals were sacrificed after 24 or 72 hours, respectively. Both TAK-063 doses enhanced neurological function, reduced infarct volume, increased neuronal survival, reduced brain edema, and increased blood-brain barrier integrity, alongside cerebral microcirculation improvements. Post-ischemic neuroprotection was associated with increased phosphorylation (i.e., activation) of pro-survival Akt, Erk-1/2 and GSK-3α/β, decreased phosphorylation (i.e., activation) of pro-survival mTOR, increased HIF-1α, MMP-9 and anti-apoptotic Bcl-xL abundance, and reduced pro-apoptotic Bax abundance. Interestingly, PDE10A inhibition reduced inflammatory cytokines/chemokines, including IFN-γ and TNF-α, analyzed by planar surface immunoassay. In addition, liquid chromatography-tandem mass spectrometry revealed 40 proteins were significantly altered by TAK-063. Our study established PDE10A as a target for ischemic stroke therapy.

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