The differential effects of FTY720 on functional recovery and infarct size following myocardial ischaemia/ reperfusion

Vuuren, Derick van; Marais, Elizabeth M.; Genade, Sonia; Lochner, Amanda

doi:10.5830/cvja-2016-039

Cited by 6 publications

(3 citation statements)

References 76 publications

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“…FTY720 is a lipophilic immunomodulatory sphingosine-1-phosphate (S1P) analog, which is now used for treatment of multiple sclerosis and prevents T-lymphocyte egress from lymphoid organs ( 244 ). FTY720 reduces R/I to the other organs such as kidney, liver, and heart in the laboratory ( 221 , 222 ). Studies in cerebral ischemia have similarly shown reduction in I/R injury and improvement in neurological function ( 223 ).…”

Section: Anti-inflammatory Treatmentsmentioning

confidence: 99%

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

2017

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While the mainstay of acute stroke treatment includes revascularization via recombinant tissue plasminogen activator or mechanical thrombectomy, only a minority of stroke patients are eligible for treatment, as delayed treatment can lead to worsened outcome. This worsened outcome at the experimental level has been attributed to an entity known as reperfusion injury (R/I). R/I is occurred when revascularization is delayed after critical brain and vascular injury has occurred, so that when oxygenated blood is restored, ischemic damage is increased, rather than decreased. R/I can increase lesion size and also worsen blood barrier breakdown and lead to brain edema and hemorrhage. A major mechanism underlying R/I is that of poststroke inflammation. The poststroke immune response consists of the aberrant activation of glial cell, infiltration of peripheral leukocytes, and the release of damage-associated molecular pattern (DAMP) molecules elaborated by ischemic cells of the brain. Inflammatory mediators involved in this response include cytokines, chemokines, adhesion molecules, and several immune molecule effectors such as matrix metalloproteinases-9, inducible nitric oxide synthase, nitric oxide, and reactive oxygen species. Several experimental studies over the years have characterized these molecules and have shown that their inhibition improves neurological outcome. Yet, numerous clinical studies failed to demonstrate any positive outcomes in stroke patients. However, many of these clinical trials were carried out before the routine use of revascularization therapies. In this review, we cover mechanisms of inflammation involved in R/I, therapeutic targets, and relevant experimental and clinical studies, which might stimulate renewed interest in designing clinical trials to specifically target R/I. We propose that by targeting anti-inflammatory targets in R/I as a combined therapy, it may be possible to further improve outcomes from pharmacological thrombolysis or mechanical thrombectomy.

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Section: Anti-inflammatory Treatmentsmentioning

confidence: 99%

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

2017

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“…The effect of FTY720 includes the induction of systemic lymphopenia, inhibition of inflammatory responses, and downregulation of intravascular adhesion molecules. Recently, several studies have shown that FTY720 protects organs from I/R injury, such as the liver [8,9], kidney [10,11], heart [12][13][14], and brain [15][16][17][18][19]. However, the mechanisms underlying the BBBprotective effects of FTY720 and time course of inflammatory modulation have not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Higashikawa

Yasui

et al. 2020

Transl. Stroke Res.

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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 [ 18 F]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.

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“…Egom et al, ). In a study by van Vuuren, Marais, Genade, and Lochner (), the effect of FTY720 on I/R injury has been investigated, and their results have demonstrated that FTY720 shows divergent effects in a dose‐dependent manner and time of administration. Another notable point is that high morbidity and mortality in cardiac transplant patients is related to I/R injury (Murata et al, ; Tanaka et al, ).…”

Section: Role Of S1p In Ischemia/reperfusion Injurymentioning

confidence: 99%

The role of sphingosine 1 phosphate in coronary artery disease and ischemia reperfusion injury

Mihanfar

Nejabati

Fattahi

et al. 2018

Journal Cellular Physiology

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Coronary artery disease (CAD) is a common cause of morbidity and mortality worldwide. Atherosclerotic plaques, as a hallmark of CAD, cause chronic narrowing of coronary arteries over time and could also result in acute myocardial infarction (AMI). The standard treatments for ameliorating AMI are reperfusion strategies, which paradoxically result in ischemic reperfusion (I/R) injury. Sphingosine 1 phosphate (S1P), as a potent lysophospholipid, plays an important role in various organs, including immune and cardiovascular systems. In addition, high‐density lipoprotein, as a negative predictor of atherosclerosis and CAD, is a major carrier of S1P in blood circulation. S1P mediates its effects through binding to specific G protein‐coupled receptors, and its signaling contributes to a variety of responses, including cardiac inflammation, dysfunction, and I/R injury protection. In this review, we will focus on the role of S1P in CAD and I/R injury as a potential therapeutic target.

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The differential effects of FTY720 on functional recovery and infarct size following myocardial ischaemia/ reperfusion

Cited by 6 publications

References 76 publications

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke

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

The role of sphingosine 1 phosphate in coronary artery disease and ischemia reperfusion injury

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