Sphingosine-1-Phosphate: Its Pharmacological Regulation and the Treatment of Multiple Sclerosis: A Review Article

Abstract

Sphingosine-1-phosphate (S1P), via its G-protein-coupled receptors, is a signaling molecule with important regulatory properties on numerous, widely varied cell types. Five S1P receptors (S1PR1-5) have been identified, each with effects determined by their unique G-protein-driven downstream pathways. The discovery that lymphocyte egress from peripheral lymphoid organs is promoted by S1P via S1PR-1 stimulation led to the development of pharmacological agents which are S1PR antagonists. These agents promote lymphocyte sequestration and reduce lymphocyte-driven inflammatory damage of the central nervous system (CNS) in animal models, encouraging their examination of efficacy in the treatment of multiple sclerosis (MS). Preclinical research has also demonstrated direct protective effects of S1PR antagonists within the CNS, by modulation of S1PRs, particularly S1PR-1 and S1PR-5, and possibly S1PR-2, independent of effects upon lymphocytes. Three of these agents, fingolimod, siponimod and ozanimod have been approved, and ponesimod has been submitted for regulatory approval. In patients with MS, these agents reduce relapse risk, sustained disability progression, magnetic resonance imaging markers of disease activity, and whole brain and/or cortical and deep gray matter atrophy. Future opportunities in the development of more selective and intracellular S1PR-driven downstream pathway modulators may expand the breadth of agents to treat MS.

Sphingosine-1-Phosphate Receptor 3 Potentiates Inflammatory Programs in Normal and Leukemia Stem Cells to Promote Differentiation

“…FTY720, a prodrug whose phosphorylation generates the S1P mimetic FTY720-phosphate, possesses both agonist and antagonist activity for four S1P receptors including S1PR3. Clinically known as fingolimod, FTY720 is used for treatment of relapse-remitting multiple sclerosis patients, with the possibility of rapid repurposing for AML (18,21). Treatment of mice bearing primary AML xenografts with FTY720 resulted in decreased leukemia burden for three of twelve patient samples tested ( Fig.…”

“…Notably, within the murine system S1P signaling via S1PR1 regulates Blymphopoiesis and neuroinflammation (20). In humans, S1P receptor modulators are used to target immune cells to treat multiple sclerosis, a chronic inflammatory disease (18,(21)(22)(23). Aside from mature lineage cells, inflammation has pleiotropic effects within primitive hematopoietic cells, governing both lineage determination and HSC stemness functions 10,11 .…”

An Overview of the Efficacy and Safety of Ozanimod for the Treatment of Relapsing Multiple Sclerosis

“…S1PR modulators can readily cross the blood-brain barrier (BBB), thereby allowing the establishment of a direct interaction with CNS receptors; this interaction may be partly responsible for the therapeutic benefit demonstrated by this class of drugs. 7 …”

“…6 S1PR modulators can readily cross the blood-brain barrier (BBB), thereby allowing the establishment of a direct interaction with CNS receptors; this interaction may be partly responsible for the therapeutic benefit demonstrated by this class of drugs. 7 The modulation of S1PR in the neurons, microglia, astrocytes, and oligodendrocytes has been hypothesized to promote myelin regeneration and to prevent the occurrence of synaptic defects, ultimately preventing neuronal damage. 8 These effects are thought to be attributable not only to the interaction with the subtype 1 receptor, but also with the subtype 5 receptor that is mainly expressed on oligodendrocytes in white matter tracts and on brain endothelial cells.…”

OCT Analysis in Patients with Relapsing-Remitting Multiple Sclerosis during Fingolimod Therapy: 2-Year Longitudinal Retrospective Study

“…Among them, fingolimod, the first oral drug, was approved in 2010 after showing positive results in two phase III randomized clinical trials conducted on relapsing-remitting MS (RR-MS) patients [11,12]. Fingolimod is a pro-drug that, after phosphorylation, acts as a modulator of the sphingosine1-phosphate receptor by reducing the exit of lymphocytes from lymphoid tissues and consequent self-aggression into the central nervous system [13,14].…”