sphingosine-1-phosphate and Ischemic-Stroke

Sphingosine 1-phosphate (S1P) is a bioactive metabolite of sphingomyelin. S1P activates a series of signaling cascades by acting on its receptors S1PR1-3 on endothelial cells (ECs), which plays an important role in endothelial barrier maintenance, anti-inflammation, antioxidant and angiogenesis, and thus is considered as a potential therapeutic biomarker for ischemic stroke, sepsis, idiopathic pulmonary fibrosis, cancers, type 2 diabetes and cardiovascular diseases. We presently review the levels of S1P in those vascular and vascular-related diseases. Plasma S1P levels were reduced in various inflammation-related diseases such as atherosclerosis and sepsis, but were increased in other diseases including type 2 diabetes, neurodegeneration, cerebrovascular damages such as acute ischemic stroke, Alzheimer's disease, vascular dementia, angina, heart failure, idiopathic pulmonary fibrosis, community-acquired pneumonia, and hepatocellular carcinoma. Then, we highlighted the molecular mechanism by which S1P regulated EC biology including vascular development and angiogenesis, inflammation, permeability, and production of reactive oxygen species (ROS), nitric oxide (NO) and hydrogen sulfide (H₂S), which might provide new ways for exploring the pathogenesis and implementing individualized therapy strategies for those diseases.

Topics: Diabetes Mellitus, Type 2; Endothelial Cells; Humans; Idiopathic Pulmonary Fibrosis; Inflammation; Ischemic Stroke; Lysophospholipids; Sepsis; Sphingosine

Sphingosine 1-phosphate (S1P) is an important lipid biomolecule that exerts pleiotropic cellular actions as it binds to and activates its five G-protein-coupled receptors, S1P

Topics: Animals; Brain Damage, Chronic; Brain Ischemia; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Fingolimod Hydrochloride; Humans; Infarction, Middle Cerebral Artery; Inflammation; Ischemic Stroke; Lysophospholipids; Neovascularization, Physiologic; Nerve Tissue Proteins; Neuroprotective Agents; Phosphotransferases (Alcohol Group Acceptor); Rats; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P

Topics: Aldehyde-Lyases; Alzheimer Disease; Animals; Cerebrovascular Disorders; Clinical Trials as Topic; Dementia, Vascular; Drug Delivery Systems; Drug Evaluation, Preclinical; Fingolimod Hydrochloride; Humans; Infarction, Middle Cerebral Artery; Inflammation; Ischemic Stroke; Lysophospholipids; Mice; Mice, Knockout; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

Finding novel and effective drugs for the treatment of ischemic stroke is warranted because there is not a definitive treatment for this prevalent disease. Due to the relevance between the sphingosine 1-phosphate (S1P) receptor and several neurological diseases including ischemic stroke, it seems that fingolimod (FTY720), as an agonist of S1P receptor, can be a useful therapeutic strategy in these patients. FTY720 is the first oral drug approved by the US food and drug administration for the treatment of multiple sclerosis. Three important mechanisms for neuroprotective effects of FTY720 have been described. First, the functional antagonistic mechanism that is associated with lymphopenia and reduced lymphocytic inflammation. This effect results from the down-regulation and degradation of lymphocytes' S1P receptors, which inhibits lymph node lymphocytes from entering the bloodstream. Second, a functional agonistic activity that is mediated through direct effects via targeting S1P receptors on the membrane of various cells including neurons, microglia, oligodendrocytes, astrocytes, and endothelial cells of blood vessels in the central nervous system (CNS), and the third, receptor-independent mechanisms that are displayed by binding to specific cellular proteins that modulate intracellular signaling pathways or affect epigenetic transcriptions. Therefore, we review these mechanisms in more detail and describe the animal model and in clinical trial studies that support these three mechanisms for the neuroprotective action of FTY720 in ischemic stroke.

Topics: Animals; Brain Ischemia; Endothelial Cells; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Ischemic Stroke; Lysophospholipids; Propylene Glycols; Receptors, Lysosphingolipid; Sphingosine; Stroke

Long-chain ceramides are associated with the mechanisms and clinical outcomes of acute ischemic stroke (AIS). This study aimed to investigate the plasma ceramides and sphingosine-1-phosphate in AIS patients undergoing endovascular thrombectomy (EVT) and their associations with outcomes.. Plasma samples were collected from 75 AIS patients who underwent EVT before (T1), immediately after (T2), and 24 h after (T3) the procedures and 19 controls that were matched with age, sex, and co-morbidities. The levels of ceramides with different fatty acyl chain lengths and sphingosine-1-phosphate were measured by UHPLC-ESI-MS/MS. A poor outcome was defined as a modified Rankin Scale score of 3-6 at 3 months after stroke.. The plasma levels of long-chain ceramides Cer (d18:1/16:0) at all three time points, Cer (d18:1/18:0) at T1 and T3, and Cer (d18:1/20:0) at T1 and very-long-chain ceramide Cer (d18:1/24:1) at T1 were significantly higher in AIS patients than those in the controls. In contrast, the plasma levels of sphingosine-1-phosphate in AIS patients were significantly lower than those in the controls at all three time points. Among the AIS patients, 34 (45.3%) had poor functional outcomes at 3 months poststroke. Multivariable analysis showed that higher levels of Cer (d18:1/16:0) and Cer (d18:1/18:0) at all three time points, Cer (d18:1/20:0) at T1 and T2, and Cer (d18:1/24:0) at T2 remained significantly associated with poor functional outcomes after adjustment for potential confounding factors.. Plasma ceramides were elevated early in AIS patients with acute large artery occlusion. Furthermore, Cer (d18:1/16:0) and Cer (d18:1/18:0) could be early prognostic indicators for AIS patients undergoing EVT.

Topics: Biomarkers; Ceramides; Endovascular Procedures; Humans; Ischemic Stroke; Sphingolipids; Stroke; Tandem Mass Spectrometry

Cardiovascular diseases like stroke cause changes to sphingolipid mediators like sphingosine 1-phosphate (S1P) or its ceramide analogs, which bear the potential to either alleviate or exacerbate the neurological damage. Therefore, the precise identification of alterations within the sphingolipidome during ischemic stroke (IS) and hemorrhagic transformation (HT) harbors a putative therapeutic potential to orchestrate local and systemic immunomodulatory processes. Due to the scarcity of research in this field, we aimed to characterize the sphingolipidome in IS and HT.. C57BL/6 mice underwent middle cerebral artery occlusion (MCAO) and specimens of the peri-infarct tissue were taken for sphingolipid profiling.. Ischemic stroke resulted in reduced S1P whilst ceramides were elevated six hours post ischemia onset. However, these differences were nearly revoked at 24 hours post ischemia onset. Moreover, the topmost S1P and ceramide levels were linked to the presence of HT after MCAO. In this study we show the characterization of the sphingolipidomic landscape of the peri-infarct tissue after ischemic stroke and HT. Especially, highest values of S1P, C 18 lactosylceramide, C 18 glucosylceramide, and C 24:1 ceramide were nearly entirely expressed by mice with HT.. Our results warrant further investigations into the immunomodulatory consequences of altered sphingolipid species for the development of HT after IS.

Topics: Animals; Brain Ischemia; Ceramides; Disease Models, Animal; Infarction, Middle Cerebral Artery; Ischemic Stroke; Mice; Mice, Inbred C57BL; Sphingolipids; Stroke

The aim of this study was to examine whether sphingosine-1-phosphate (S1P) levels in patients with acute stroke are associated with stroke severity and outcome.. In a prospective stroke cohort (MARK-STROKE), 374 patients with acute ischemic stroke or transient ischemic attack were enrolled (mean age: 67.9±13.0 years, sex: 64.7% male), and serum-S1P at admission was analyzed with tandem mass spectrometry. In addition to cross-sectional analyses, 79 adverse events (death, stroke, myocardial infarction, rehospitalization) were recorded in 270 patients during follow-up. Regression analyses were adjusted for age, sex, low-density lipoprotein cholesterol, and vascular risk factors. Results were validated in an independent stroke cohort with 219 patients with acute ischemic stroke (CIRCULAS).. Low serum-S1P was associated with higher National Institutes of Health Stroke Scale score at admission and with anterior circulation nonlacunar infarcts determined by multivariate regression analyses. During a follow-up of 294±170 days, patients with S1P in the lowest tertile (<1.33 µmol/L) had more adverse events (Kaplan-Meier analysis,. Our findings imply a detrimental role of low S1P levels in acute stroke and therefore underpin the therapeutic potential of S1P-mimics.

Topics: Aged; Aged, 80 and over; Biomarkers; Brain Ischemia; Female; Humans; Ischemic Stroke; Lysophospholipids; Male; Middle Aged; Prognosis; Sphingosine

Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P. To address roles and mechanisms of engagement of endothelial cell S1P. Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P. This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P

Topics: Animals; Blood-Brain Barrier; Cerebral Arteries; Cerebrovascular Circulation; Disease Models, Animal; Endothelial Cells; Female; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Ischemic Stroke; Lysophospholipids; Male; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Microcirculation; Neuroprotective Agents; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors; Vascular Patency