Sphingosine 1-Phosphate Receptors in Cerebral Ischemia.

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, S1P1-5. Through these receptors, S1P can mediate diverse biological activities in both healthy and diseased conditions. S1P is produced by S1P-producing enzymes, sphingosine kinases (SphK1 and SphK2), and is abundantly present in different organs, including the brain. The medically important roles of receptor-mediated S1P signaling are well characterized in multiple sclerosis because FTY720 (Gilenya™, Novartis), a non-selective S1P receptor modulator, is currently used as a treatment for this disease. In cerebral ischemia, its role is also notable because of FTY720's efficacy in both rodent models and human patients with cerebral ischemia. In particular, some of the S1P receptors, including S1P1, S1P2, and S1P3, have been identified as pathogenic players in cerebral ischemia. Other than these receptors, S1P itself and S1P-producing enzymes have been shown to play certain roles in cerebral ischemia. This review aims to compile the current updates and overviews about the roles of S1P signaling, along with a focus on S1P receptors in cerebral ischemia, based on recent studies that used in vivo rodent models of cerebral ischemia.

Preclinical and Clinical Evidence for the Involvement of Sphingosine 1-Phosphate Signaling in the Pathophysiology of Vascular Cognitive Impairment.

Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P1-S1P5. Scrutiny of S1P-regulated pathways over the past three decades has identified important and occasionally counteracting functions in the brain and cerebrovascular system. For example, while S1P1 and S1P3 mediate proinflammatory effects on glial cells and directly promote endothelial cell barrier integrity, S1P2 is anti-inflammatory but disrupts barrier integrity. Cumulatively, there is significant preclinical evidence implicating critical roles for this pathway in regulating processes that drive cerebrovascular disease and vascular dementia, both being part of the continuum of vascular cognitive impairment (VCI). This is supported by clinical studies that have identified correlations between alterations of S1P and cognitive deficits. We review studies which proposed and evaluated potential mechanisms by which such alterations contribute to pathological S1P signaling that leads to VCI-associated chronic neuroinflammation and neurodegeneration. Notably, S1P receptors have divergent but overlapping expression patterns and demonstrate complex interactions. Therefore, the net effect produced by S1P represents the cumulative contributions of S1P receptors acting additively, synergistically, or antagonistically on the neural, vascular, and immune cells of the brain. Ultimately, an optimized therapeutic strategy that targets S1P signaling will have to consider these complex interactions.

Beneficial Effects of Fingolimod in Alzheimer's Disease: Molecular Mechanisms and Therapeutic Potential.

Alzheimer's disease (AD), the most common cause of dementia remains of unclear etiology with current pharmacological therapies failing to halt disease progression. Several pathophysiological mechanisms have been implicated in AD pathogenesis including amyloid-ß protein (Aß) accumulation, tau hyperphosphorylation, neuroinflammation and alterations in bioactive lipid metabolism. Sphingolipids, such as sphingosine-1-phosphate (S1P) and intracellular ceramide/S1P balance are highly implicated in central nervous system physiology as well as in AD pathogenesis. FTY720/Fingolimod, a structural sphingosine analog and S1P receptor (S1PR) modulator that is currently used in the treatment of relapsing-remitting multiple sclerosis (RRMS) has been shown to exert beneficial effects on AD progression. Recent in vitro and in vivo evidence indicate that fingolimod may suppress Aß secretion and deposition, inhibit apoptosis and enhance brain-derived neurotrophic factor (BDNF) production. Furthermore, it regulates neuroinflammation, protects against N-methyl-D-aspartate (NMDA)-excitotoxicity and modulates receptor for advanced glycation end products signaling axis that is highly implicated in AD pathogenesis. This review discusses the underlying molecular mechanisms of the emerging neuroprotective role of fingolimod in AD and its therapeutic potential, aiming to shed more light on AD pathogenesis as well as direct future treatment strategies.