Abstract W P251: Novel Platelet-Activating Factor Receptor Antagonists Attenuate Brain Injury after Experimental Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Nicolas G Bazan ◽  
Larissa Khoutorova ◽  
Julio Alvarez-Builla ◽  
Ludmila Belayev
Keyword(s):  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Synaptic Activity ◽  
Experimental Stroke ◽  
Vehicle Group ◽  
Receptor Antagonists ◽  
Physiological Variables ◽  
Paf Receptor

INTRODUCTION: Platelet-activating factor (PAF) is a bioactive phospholipid that regulates synaptic activity and when overproduced is a potent mediator of leukocyte functions, including platelet aggregation and inflammation. PAF concentration increases during ischemia-reperfusion and is a mediator of neurotoxicity. The inhibition of this process plays a critical role in neuronal survival. We synthesized various analogues and identified them as PAF receptor antagonists, which were then selected for in vivo experiments to evaluate anti-ischemic activity. METHODS: Physiologically controlled Sprague-Dawley rats received 2 h MCAo by poly-L-lysine-coated intraluminal suture. LAU compounds (LAU-0901, LAU-09015, LAU-09018, LAU-09019, LAU-09020 or LAU-09023; 30 mg/kg) or vehicle (45% cyclodextran) was administered IP at 2 h from onset of MCAo. Neurological status was evaluated during occlusion (at 60 min) and on day 1, 2, 3 and 7. Histopathology was carried out on day 7. RESULTS: Physiological variables were stable and showed no significant differences between groups. All LAU compounds significantly reduced the neurobehavioral deficit compared to the vehicle group, beginning from day 1 and persisting through the 7 day survival period. Histologically, the vehicle group showed large hemispheric infarcts with pan-necrosis. By contrast, LAU-treated rats showed preserved hemispheric structure and small subcortical infarcts. Treatment with LAU (LAU-0901, LAU-09015, LAU-09018, LAU-09019, or LAU-09023) significantly reduced total infarct volume compared to the vehicle group by 68%, 52%, 40%, 51% and 54%, respectively. CONCLUSION: Our results clearly indicate that novel LAU PAF receptor antagonists are highly neuroprotective on behavior and reduction of brain infarction in experimental stroke. These compounds may provide the basis for future therapeutics in patients suffering ischemic stroke.

Role of Platelet-Activating Factor in Cardiovascular Pathophysiology

2000 ◽  
Vol 80 (4) ◽  
pp. 1669-1699 ◽  
Author(s):  
Giuseppe Montrucchio ◽  
Giuseppe Alloatti ◽  
Giovanni Camussi
Keyword(s):  
Cardiovascular System ◽  
Cell Biology ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Experimental Studies ◽  
Platelet Activating Factor ◽  
Biologically Active ◽  
Endothelial Cell Migration

Platelet-activating factor (PAF) is a phospholipid mediator that belongs to a family of biologically active, structurally related alkyl phosphoglycerides. PAF acts via a specific receptor that is coupled with a G protein, which activates a phosphatidylinositol-specific phospholipase C. In this review we focus on the aspects that are more relevant for the cell biology of the cardiovascular system. The in vitro studies provided evidence for a role of PAF both as intercellular and intracellular messenger involved in cell-to-cell communication. In the cardiovascular system, PAF may have a role in embryogenesis because it stimulates endothelial cell migration and angiogenesis and may affect cardiac function because it exhibits mechanical and electrophysiological actions on cardiomyocytes. Moreover, PAF may contribute to modulation of blood pressure mainly by affecting the renal vascular circulation. In pathological conditions, PAF has been involved in the hypotension and cardiac dysfunctions occurring in various cardiovascular stress situations such as cardiac anaphylaxis and hemorrhagic, traumatic, and septic shock syndromes. In addition, experimental studies indicate that PAF has a critical role in the development of myocardial ischemia-reperfusion injury. Indeed, PAF cooperates in the recruitment of leukocytes in inflamed tissue by promoting adhesion to the endothelium and extravascular transmigration of leukocytes. The finding that human heart can produce PAF, expresses PAF receptor, and is sensitive to the negative inotropic action of PAF suggests that this mediator may have a role also in human cardiovascular pathophysiology.

Abstract 1944: Atorvastatin Reduces Intracerebral Hemorrhage after Experimental Stroke

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hazem F Elewa ◽  
Anna Kozak ◽  
David Rychly ◽  
Adviye Ergul ◽  
Reginald Frye ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Intracerebral Hemorrhage ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Methyl Cellulose ◽  
The United States ◽  
Experimental Stroke ◽  
High Risk Population ◽  
Protective Agent ◽  
Oral Gavage

Ischemic stroke is a leading cause of death and disability in the United States and diabetes mellitus is the fastest growing risk factor for stroke. In addition, hyperglycemia, which is usually associated with diabetes, tends to worsen ischemia/reperfusion injury and to induce more oxidative stress damage. Preliminary data from our laboratory showed that diabetic animals (Goto-Kakizaki rats (GKs) are more susceptible to vascular damage leading to intracerebral hemorrhage. Many studies have indicated that statins possess neuroprotective properties even when administered after the onset of ischemia. However, the acute vascular effects of statins after ischemic stroke have not been studied to date. Objective: to evaluate the efficacy and magnitude of vascular protection of acute statin therapy in both GKs and their normoglycemic controls after experimental ischemic stroke. Methods: Male Wistar (W) and GK rats (270–305 g) underwent 3 hours of middle cerebral artery occlusion (MCAO) followed by reperfusion for 21 hours. Animals were randomized to receive either atorvastatin (15mg/Kg) or methyl cellulose (0.5%), administered by oral gavage, the first dose 5 minutes after reperfusion and the second dose after 12 hours. Brain tissue was analyzed for infarct volume and hemoglobin content. In another set of Wistar rats (n=3), atorvastatin (15mg/Kg) was administered by oral gavage to compare its pharmacokinetic profile with that of humans Results: Atorvastatin-treated groups had significantly lower hemoglobin (p=0.0156) and infarct volume (p=0.0132) compared to their controls. Atorvastatin peak concentration (27–77 ng/ml) in rats’ plasma was found to be similar to that seen after 80mg/day of atorvastatin in humans. Conclusion: Atorvastatin can be a novel vascular protective agent after acute ischemic stroke especially in a high risk population like diabetics. The mechanisms through which these effects are mediated are currently being investigated.

scholarly journals FTY720 Protects Against Ischemia–Reperfusion Injury by Preventing the Redistribution of Tight Junction Proteins and Decreases Inflammation in the Subacute Phase in an Experimental Stroke Model

2020 ◽  
Vol 11 (5) ◽  
pp. 1103-1116 ◽  
Author(s):  
Zifeng Wang ◽  
Kei Higashikawa ◽  
Hironobu Yasui ◽  
Yuji Kuge ◽  
Yusuke Ohno ◽  
...  
Keyword(s):  
Cell Death ◽  
Tight Junction ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Male Rats ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Vehicle Group ◽  
Tight Junction Proteins ◽  
Junction Proteins

Abstract Injury due to brain ischemia followed by reperfusion (I/R) may be an important therapeutic target in the era of thrombectomy. FTY720, a widely known sphingosine-1-phosphate receptor agonist, exerts various neuroprotective effects. The aim of this study was to examine the protective effect of FTY720 with respect to I/R injury, especially focusing on blood–brain barrier (BBB) protection and anti-inflammatory effects. Male rats were subjected to transient ischemia and administered vehicle or 0.5 or 1.5 mg/kg of FTY720 immediately before reperfusion. Positron emission tomography (PET) with [18F]DPA-714 was performed 2 and 9 days after the insult to serially monitor neuroinflammation. Bovine and rat brain microvascular endothelial cells (MVECs) were also subjected to oxygen-glucose deprivation (OGD) and reperfusion, and administered FTY720, phosphorylated-FTY720 (FTY720-P), or their inhibitor. FTY720 dose-dependently reduced cell death, the infarct size, cell death including apoptosis, and inflammation. It also ameliorated BBB disruption and neurological deficits compared to in the vehicle group. PET indicated that FTY720 significantly inhibited the worsening of inflammation in later stages. FTY720-P significantly prevented the intracellular redistribution of tight junction proteins but did not increase their mRNA expression. These results suggest that FTY720 can ameliorate I/R injury by protecting the BBB and regulating neuroinflammation.

scholarly journals Platelet-activating Factor, a Molecular Sensor for Cellular Damage, Activates Systemic Immune Suppression

2002 ◽  
Vol 195 (2) ◽  
pp. 171-179 ◽  
Author(s):  
Jeffrey P. Walterscheid ◽  
Stephen E. Ullrich ◽  
Dat X. Nghiem
Keyword(s):  
Skin Cancer ◽  
Uv Radiation ◽  
Immune Suppression ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Cellular Damage ◽  
Uv Exposure ◽  
Delayed Type Hypersensitivity ◽  
Lipid Mediator ◽  
Paf Receptor

Ultraviolet (UV) radiation plays a critical role in the induction of nonmelanoma skin cancer. UV radiation is also immune suppressive, and the immune suppression induced by UV irradiation has been identified as a major risk factor for skin cancer induction. Previously, we showed that UV exposure activates a cytokine cascade involving prostaglandin (PG)E2, interleukin (IL)-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV exposure, especially those upstream of PGE2, are not well defined. UV-irradiated keratinocytes secrete the inflammatory phospholipid mediator, platelet-activating factor (PAF). Because PAF upregulates the production of immunomodulatory compounds, including PGE2, we tested the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression. Both UV and PAF activated cyclooxygenase (COX)-2 and IL-10 reporter gene construct transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH). Furthermore, immune suppression was blocked when UV-irradiated mice were injected with PAF receptor antagonists. In addition to the well-known role of PAF as a proinflammatory lipid mediator, we propose that the PAF receptor senses cellular damage through the recognition of PAF and/or PAF-like molecules, such as oxidized phosphatidylcholine, which activates cytokine transcription and induces systemic immune suppression.

scholarly journals Is platelet activating factor (PAF) an important mediator in bronchial asthma?

1992 ◽  
Vol 1 (6) ◽  
pp. 367-369 ◽  
Author(s):  
R. H. Gundel ◽  
H. O. Heuer ◽  
L. G. Letts
Keyword(s):  
Lung Function ◽  
Bronchial Asthma ◽  
Platelet Activating Factor ◽  
Receptor Antagonists ◽  
Primate Model ◽  
Novel Approach ◽  
Paf Receptor ◽  
Airway Responses ◽  
Preclinical Animal Models ◽  
Induced Changes

The development of selective PAF receptor antagonists may provide a novel approach to the treatment of human bronchial asthma. In preclinical animal models of human asthma, PAF receptor antagonists have been found to be efficacious in blocking antigen-induced changes in lung function. However, the majority of these models involve acute inflammatory events and transient changes in lung function and, therefore, their relevance to human asthma is questionable. In a recent study with a primate model of chronic airway inflammation and hyperresponsiveness, we have shown that treatment with a PAF receptor antagonist had no effect on reducing chronic inflammation and hyperresponsiveness. Similarly, recent studies in human asthmatics with PAF receptor antagonists have failed to show efficacy in blocking allergen-induced airway responses or to have any steroid sparing effects in patients with ongoing asthma. Thus, it seems that PAF may not be a key mediator which can be blocked and thereby provide therapy for bronchial asthma.

Abstract 3098: Docosahexaenoic Acid Protects The Brain After Experimental Stroke By Modulating Protein Phosphorylation In The Penumbra

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Tiffany N Eady ◽  
Ludmila Belayev ◽  
Larissa Khoutorova ◽  
Kristal D Atkins ◽  
Nicolas G Bazan
Keyword(s):  
Docosahexaenoic Acid ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Experimental Stroke ◽  
Omega 3 ◽  
Western Blots ◽  
Behavioral Deficit ◽  
Physiological Variables ◽  
Cell Counts ◽  
Ischemic Core

Background and purpose: Docosahexaenoic acid (DHA), a member of the omega-3 essential fatty acid family, improves behavioral deficit and reduces infarct volume and brain edema after focal cerebral ischemia in rats. We hypothesize that DHA elicits neuroprotection by inducing protective cellular cascades, which in turn lead to cell survival. We used behavioral tests in conjunction with immunohistopathology and western blots to expand our understanding of the early mechanisms responsible for DHA-induced neuroprotection. Methods: Physiologically-controlled male Sprague-Dawley rats (304-370g) received 2h middle cerebral artery occlusion (MCAo) by intraluminal suture. Animals were treated with DHA (5mg/kg, iv) or saline (5ml/kg) at 3h after the onset of stroke. Behavioral function was evaluated at 1h after occlusion onset and at 24h on a grading scale of 0-12 (0=normal and 12=maximal deficit). GFAP (reactive astrocytes), ED-1 (activated microglia/microphages), and NeuN (neurons) were analyzed in the ischemic core and the penumbra regions (A, B and C) at 4 and 24h. Western blot/immunohistochemical analysis of pAKT, pGSK, and pS6 (proteins of the AKT signaling pathway) was conducted in the core and penumbra at 4 and 24h. Results: Physiological variables were stable and showed no significant differences between groups. Behavioral deficit was significantly improved by treatment with DHA compared to vehicle at 24h (7.3±0.5 vs. 10±0; p<0.001, respectively). DHA treatment significantly reduced the number of microglia cells in penumbra regions A and C (by 86% and 76%) and increased GFAP-positive cells in penumbra regions B and C (by 53% and 51%) at 24h after stroke. There were no significant differences in expression of cell markers between groups at 4h and in the ischemic core. DHA upregulated activation of AKT compared to vehicle at 4h (36% increase in p473 AKT and 79% increase in p308 AKT) and at 24h (114% increase in p473 AKT; 98% increase in p308 AKT). DHA also increased pS6 at 4h by 160% and pGSK at 24h by 61% as compared to vehicle-treated animals. DHA-treated animals had significantly higher p308 AKT cell counts in the penumbra at 4h (region A by182%, region B by 160% and region C by 103% increase). Conclusions: DHA treatment confers behavioral improvement, reduces microglial infiltration, increases astrocytosis at 24h, activates pro-survival AKT cascades as early as 4h, and has potential for the treatment of ischemic stroke.

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