The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

Abstract

Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a pleiotropic bioactive lipid mediator capable of evoking complex immune phenomena. Studies have highlighted its importance regarding intracellular signaling cascades as well as membrane-bound S1P receptor (S1PR) engagement in various clinical conditions. In neurological disorders, the S1P–S1PR axis is acknowledged in neurodegenerative, neuroinflammatory, and cerebrovascular disorders. Modulators of S1P signaling have enabled an immense insight into fundamental pathological pathways, which were pivotal in identifying and improving the treatment of human diseases. However, its intricate molecular signaling pathways initiated upon receptor ligation are still poorly elucidated. In this review, the authors highlight the current evidence for S1P signaling in neurodegenerative and neuroinflammatory disorders as well as stroke and present an array of drugs targeting the S1P signaling pathway, which are being tested in clinical trials. Further insights on how the S1P–S1PR axis orchestrates disease initiation, progression, and recovery may hold a remarkable potential regarding therapeutic options in these neurological disorders.

Lipid metabolism in cancer progression and therapeutic strategies

“…It has been suggested that the balance between levels of ceramide and S1P plays an important role in determining cell survival and apoptosis. The regulatory effect of S1P in cell physiology and pathology is driven through their binding to G protein‐coupled S1P receptors (S1PRs) leading to the activation of downstream signaling pathways including Akt and ERK1/2 70 . In addition, intracellular S1P can epigenetically regulate gene expression 71 .…”

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

“…S1P level is regulated also by S1P-degrading enzymes, such as S1P phosphatases (SPPs) that convert S1P to sphingosine (Sph) and S1P lyase (SPL), which terminally cleaves this sphingolipid to hexadecenal and ethanolamine phosphate [115]. Nowadays, compounds that mimic S1P action are recognized as promising in studies concerning a subset of neuronal diseases [116][117][118]. On the other hand, SPL-encoding gene mutation leading to the inborn error, referred to as sphingosine phosphate lyase insufficiency syndrome (SPLIS), could be toxic to neurons [119].…”

A Sphingosine 1-Phosphate Gradient Is Linked to the Cerebral Recruitment of T Helper and Regulatory T Helper Cells during Acute Ischemic Stroke

“…The regulation of a wide range of cellular processes was described, including endocytosis, intracellular trafficking of molecular constituents, and signal transduction by membrane receptors [ 1 , 2 ]. Recent insights into the molecular mechanisms of action provide increasing evidence for the complex pathways of sphingolipid metabolism in the pathogenesis of multiple diseases including cancer, diabetes, neurodegenerative disorders, autoimmune diseases, and stroke [ 3 , 4 , 5 , 6 , 7 ]. Fingolimod represents an unselective functional antagonist to sphingosine 1-phosphate receptors (S1P R ) resulting in S1P R downregulation upon S1P R engagement [ 8 , 9 ].…”