Serum Sphingosine-1-Phosphate Levels Are Associated With Severity and Outcome in Patients With Cerebral Ischemia

Abstract

Background and Purpose: 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. Methods: 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). Results: 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, P =0.048 for trend). In adjusted Cox regression analysis, the lowest S1P tertile was associated with a worse outcome after stroke (hazard ratio, HR 0.51 [95% confidence interval 0.28–0.92]). Results were confirmed in an independent cohort, ie, low S1P levels were associated with higher National Institutes of Health Stroke Scale, larger infarct volumes and worse outcome after 90 days (β-coefficient: –0.03, P =0.026; β-coefficient: −0.099, P =0.009 and odds ratio 0.52 [0.28–0.96], respectively). Conclusions: Our findings imply a detrimental role of low S1P levels in acute stroke and therefore underpin the therapeutic potential of S1P-mimics.

Spinal Stroke: Outcome Attenuation by Erythropoietin and Carbamylated Erythropoietin and Its Prediction by Sphingosine-1-Phosphate Serum Levels in Mice

“…It is possible that high levels in the early phase after SCI are crucial for the subsequent neurological outcome. This finding is in line with previous reports in clinical and experimental ischemic stroke [ 13 , 14 ]. In mice that were subjected to middle cerebral artery occlusion, immediate activation of endothelial S1PR1 prevents endothelial leakage and reduces ischemic damage and neuronal death [ 14 ].…”

“…Furthermore, sphingosine-1-phosphate (S1P) was the focus of research on the neurological outcomes after ischemic stroke and SCI [ 13 , 14 , 15 ]. It was reported that S1P is elevated at the site of SCI in rats and enhances the plasticity of neuronal progenitor cells [ 16 ].…”

Serum Sphingosine 1-Phosphate as a Biomarker for Post-Stroke Cognitive Impairment

“…In this study we tried to explore the relation between S1P serum levels and post-stroke cognitive impairment, one of the most devastating complications of cerebrovascular stroke. As was reported in previous studies (4,8) , serum S1P level was apparently lower in patients with acute ischemic stroke than healthy controls. Furthermore, low serum S1P level was associated with more severe neurological disability and impaired cognitive at 3 months follow-up after ischemic stroke.…”

“…Moreover, after brain infarction, hypoxic ischemic mitochondrial dysfunction, excitotoxicity, and oxidative stress damage promoting the breakdown of vascular endothelial cells, resulting in disturbance of both function and integrity of the endothelial barrier (9,14) . Hence, S1P receptor agonists have been studied in various experimental stroke models and also in acute ischemic stroke patients and was found to be useful by regulating endothelial adherent junctions, cerebrovascular responses, and blood-brain barrier functions by activation of S1P signaling (8,15,16) . In line with our results, decreased serum S1P levels were associated with adverse events after acute ischemic stroke.…”

Two-photon microscopy in vivo reveals brain vessel type-specific loss of glycocalyx caused by apoM/S1P signaling impairment

“…Increased shedding of gcx accompanies aging [55,56] and pathologies affecting vascular function, e.g., stroke [10,57], sepsis [58,59] and diabetes [60]. These conditions have a common denominator, impaired S1P signaling [61][62][63][64][65] and all feature an increase in AMT [8,9,[11][12][13]66]. The joint occurrence of S1P signaling deficits, gcx loss and AMT increase may suggest a causal relationship, but these features have never been cross-examined in the same experimental setting.…”