Research progress of sphingosine 1-phosphate and its signal transduction in central nervous system diseases

BEN Xin-yu, YI Xi-nan, LI Qi-fu?

1. Department of Neurology, First Affiliated Hospital of Hainan Medical College, Haikou 570102, China

2. Key Laboratory of Tropical Brain Science Research and Transformation in Hainan Province, Haikou 571199, China

Keywords:

ABSTRACT Sphingosine 1-phosphate (S1P), as a sphingolipid metabolite, has become a key substance in regulating various physiological processes, involved in differentiation, proliferation,migration, morphogenesis, cytoskeleton formation, adhesion, apoptosis, etc.process.Sphingosine 1-phosphate can not only activate the S1P-S1PR signaling pathway by binding to the corresponding receptors on the cell membrane, but also play a role in the cell.In recent years, studies have found that there is a certain relationship between its level changes and the occurrence and development of central nervous system diseases.This article reviews the latest knowledge of sphingosine-1-phosphate in the occurrence and treatment of nervous system diseases, and further clarifies its molecular mechanism in the treatment and development of central nervous system diseases.

Sphingosine 1-phosphate (S1P) is a bioactive lipid that is produced by the conversion of ceramide to sphingosine through the phosphorylation of sphingosine by sphingosine kinase (SphK) [1].S1P can participate in various physiological activities inside cells and can also be translocated outside cells and bind to S1P receptors(S1PR) on cells[2].S1P S1P acts in an autocrine or paracrine manner through five S1P-specific cell surface G protein-coupled receptors(S1PR1-S1PR5) to regulate cell proliferation and apoptosis[3-6].S1P promotes proliferation and prevents apoptosis through activation of the PI3K/Akt pathway and the Ras/extracellular signal-regulated kinase (ERK) pathway by these receptors[7-8].In addition, S1P can activate protein kinase C to inhibit ceramide-mediated apoptosis and counteract ceramide-induced activation of stress-activated protein kinase (SAPK/JNK)[9].These evidences suggest that S1P plays a crucial role in the regulation of cell proliferation and apoptosis.

SphK, the key enzyme that phosphorylates sphingosine to S1P,consists of two isoforms, SphK1 and SphK2.Cytokine-mediated activation of SphK1 leads to the phosphorylation of sphingosine,resulting in the intracellular production of S1P, which is then transported out of the cell by sphingolipid transporter 2 (SPNS2)[10].SphK2 is located mainly in the mitochondria and nucleus,and its phosphorylation of S1P produced by sphingosine in mitochondria interacts with inhibin 2 to regulate complex IV assembly and respiration[11].Intracellular S1P acts through a variety of enzymatic reactions at different cellular locations such as the endoplasmic reticulum, mitochondria and nucleus[12-13].In conclusion, S1P produced by SphK1 acts both intracellularly and mediates intercellular signaling, while S1P produced by SphK2 regulates cellular functions only intracellularly.

1.Function of sphingosine 1-phosphate in the central nervous system

The brain has the highest level of S1P in the human body and plays an important physiological function in the central nervous system[14].Five S1P receptors have been identified, including S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5, four of which (S1PR1,S1PR2, S1PR3, and S1PR5) are expressed in the CNS[15-16].S1PR5 is most highly expressed in the human corpus callosum, whereas S1PR1 is more highly expressed in the mouse frontal cortex and corpus callosum[17].In the CNS, S1PR1 is expressed by astrocytes,microglia, oligodendrocytes, and neurons, and dysregulation of S1P may lead to physiological dysfunction in a variety of CNS cells, thereby promoting the development of neurological disorders[18].A recent study showed that exogenously added S1P increased the viability of SH-SY5Y through a S1P (1,3) receptor-dependent mechanism[19].Numerous studies have shown that decreased S1P levels and accumulation of ceramide are proportional to the degree of cognitive impairment, intellectual loss and neuronal loss[20-22].With the progressive study of sphingolipid metabolism in the nervous system, the specific functions of S1P in the central nervous system and its mechanisms are well known.

S1P is able to regulate neurotransmitter release and cell membrane excitability in synaptic transmission and also affects memory formation by modulating synaptic strength in hippocampal neurons[23-24].In addition to its effects on neurons, S1P plays an important role in the physiological processes of glial cells.Notably, S1P usually plays an unfavorable role in the effects of glial cells.For example, the addition of exogenous S1P to activated microglia causes increased release of pro-inflammatory cytokines, which leads to neuroinflammation[25].In addition, S1P promotes IL-1-induced IL-6 expression in astrocytes via S1PR1 and inhibits chemokine CCL-5 in a S1PR2-dependent mechanism[26].The administration of physiological concentrations of S1P to astrocytes induces neuronal degeneration, whereas the direct addition of S1P to neurons did not cause any changes[27].It is the inconsistent role of S1P in neurons and glial cells that makes its use in the therapeutic field of neurological diseases need to be further explored.

2.Sphingosine 1-phosphate in neurodegenerative diseases

Neurodegenerative diseases are usually characterized by intracellular or extracellular aggregation of misfolded proteins and include Parkinson’s disease (PD), Alzheimer’s disease (AD),Huntington’s disease (HD), amyotrophic lateral sclerosis, and multiple sclerosis (MS), etc[28-31].Currently, a growing number of studies have found evidence for the involvement of S1P signaling in the development of neurodegenerative diseases, and a series of drugs targeting the S1P signaling pathway have emerged on the basis of these studies, some of which are already being tested in clinical trials[32].

2.1 Effects of S1P signaling on AD

AD as the most common neurodegenerative disease has been the focus of research in neuroscience, and the role of S1P in the development of AD has received widespread attention.It is well known that Aβ protein deposition is one of the mechanisms underlying the development of Alzheimer’s disease[33].Numerous studies have confirmed that upregulation of S1P can reduce the deposition of Aβ proteins and thus improve the progression of AD[34-35].Numerous studies have found elevated ceramide levels and decreased sphingomyelin and S1P levels in the brain tissue of AD patients[36-37].It has also been suggested that the downregulation of S1P may be a consequence of the deposition of Aβ proteins after AD, which leads to apoptosis and accelerates the development of AD[38-39].Couttas et al.found that the brain exhibits upregulation of S1P cleaving enzyme SGPL1 and S1P metabolic phosphatase expression after the onset of AD, thereby downregulating S1P [37,40].However, with the increasing understanding of S1P, it has been found that upregulation of S1P in some specific situations may have the opposite effect.For example, Dominguez’s study found that increased S1P in the nucleus may have led to the deposition of Aβ protein after the balance of SphK2 in the cytoplasm and nucleus was disrupted[41].In addition to this, a study by Zhong noted that Aβ activates Spns2, which translocates S1P out of the cell, leading to S1P binding to S1PR1, and S1P binding to S1P1R followed by induction of pro-inflammatory cytokine secretion from microglia through an NF-κB-dependent mechanism, resulting in decreased cognitive function in mice[42].These evidences suggest that S1P is involved in the development of AD through multiple mechanisms,but whether it mainly plays a role in inhibiting neuronal apoptosis or promoting neuroinflammation during AD development still needs further discussion, and under which circumstances it can play a protective role is unknown.

2.2 Effects of S1P signaling on PD

Parkinson’s disease (PD) is the second most common and serious neurodegenerative disease after AD, and the current clinical treatment is not satisfactory[43-44].With the continuous research on PD, it has been found that the pathological mechanisms causing the development of PD mainly include mitochondrial dysfunction, increased oxidative stress, inflammation, synaptic nuclear protein aggregation, and neuronal apoptosis[45].sphK, a key enzyme regulating the production of S1P as a major product of the sphingolipid metabolic pathway, has been shown to play an important role in processes such as oxidative stress and neuronal apoptosis in PD[46].In addition, Yousefi-Ahmadipour and Graham in their study on S1P found the existence of ceramide metabolic pathway in mitochondria and that apoptosis caused by decreased S1P is associated with altered mitochondrial function[11,47].A recent study showed that S1P levels were lower in patients with PD than in normal healthy populations and that decreased S1P levels were strongly associated with reduced motor function and accelerated motor decline in individuals with PD[48].Reduced expression of SphK1 and SphK2 was found in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson’s mouse model[49-50].All of these studies suggest that S1P is involved in the onset and development of PD through multiple pathways.A recent review pointed out that researchers related to PD believe that lipid metabolism studies are changing the traditional treatment paradigm of PD and may be able to provide new solutions for the treatment of PD by altering the expression of S1P-related receptors or through the regulation of key S1P-related enzymes[51].

2.3 Effects of S1P signaling on HD

Huntington’s disease (HD) is a rare dominantly inherited disorder characterized by progressive striatal and cortical degeneration with some degree of motor, cognitive, and behavioral impairment[52].Much evidence in recent years suggests that in vivo imbalance of lipids (including cholesterol, fatty acids and phospholipids) may be responsible for the pathogenesis of HD[53-54].The sphingolipid metabolic pathway, one of the important metabolic pathways of lipid metabolism, has also been shown to be closely associated with the development of HD.Di’s study found that in the striatum of the HD R6/2 mouse model, the expression of SphK1 was downregulated, the expression of SphK2 was upregulated, and S1P levels were reduced.In contrast, SphK2 expression was normal in the striatum of HD patients[55].Pirhaji found that THI could improve the survival of HD neurons by inhibiting S1P lyase 1 (SGPL1) and inhibit histone deacetylase activity[56].Moruno found that in the Huntington’s disease neuronal model, inhibition of S1P cleavage enzyme protected neurons from mutant Huntington protein-induced neurotoxicity[57].All of this evidence suggests that increasing S1P levels by activating SphK1 or inhibiting SGPL1, for example, may play a beneficial role in the treatment of HD.

2.4 Effects of S1P signaling on MS

Multiple sclerosis (MS) is a T-cell-mediated autoimmune disease of the central nervous system that may lead to permanent disability in young people and is usually caused by an interaction between genetic susceptibility and environmental factors[58-59].It has been found that S1P signaling in the CNS mediates the pathological processes of MS such as astrocyte proliferation and demyelination[60].Furthermore, blockade of the S1P-S1P receptor signaling system leads to a significant decrease in circulating lymphocytes,and therefore drugs that functionally antagonize S1P receptors may attenuate the development of MS by reducing circulating lymphocyte levels[61].Since the role of S1PRs in the development of MS is relatively clear, S1P receptor modulators (fingolimod, sympomod,ozanimod, and bonimod) are now approved for the treatment of MS in some countries[62].As early as 2008, a study found that the oral sphingosine analogue FTY720 was effective in reducing disease activity in MS without more intense adverse effects[63].

Tab 1 Changes in S1P and its associated proteins in selected neurodegenerative diseases

3.Study of sphingosine 1-phosphate in ischemic injury of the central nervous system

Stroke, the second most fatal and disabling disease in the world,generates a huge economic burden worldwide, with 87% of strokes being ischemic in nature[64-65].Current treatment for ischemic stroke mostly relies on thrombolysis and mechanical recanalization in the acute phase, which often increases the risk of death and disability in some ischemic stroke patients due to ineffective treatment[66].Therefore, the search for a more effective treatment for ischemic stroke has been a hot topic of research in recent years.

A large number of studies in recent years have shown that S1P conduction pathway plays a role in the treatment of ischemic stroke,and it improves the development of ischemic stroke through various mechanisms[67-68].It has also been found that serum S1P levels are closely related to the severity of patients with cerebral ischemia, with more adverse events occurring in patients with lower S1P levels[69].In addition, in an analysis of serum S1P in patients with ischemic and hemorrhagic stroke, Liu found that decreased serum S1P was strongly associated with early acute ischemic stroke, whereas no significant association was found with S1P levels in patients with hemorrhagic stroke[70].(BBB) and promoting neural repair[71].For example, Eri Iwasawa found that in a mouse model of acute ischemic stroke, selective agonism of S1PR1 enhances soft brain collateral circulation through phosphorylation of the endothelial nitric oxide synthase eNOS, promotes postischemic angiogenesis, enhances blood brain barrier integrity, and thereby reduces infarct volume[72].model treatment with reduced proliferation of responsive astrocytes,altered synaptic plasticity and upregulation of neurotrophic factor VEGFα expression[73].All these evidences suggest a role of S1P conduction pathway in the treatment of ischemic stroke.Notably,because inflammation is both harmful and beneficial at certain stages after stroke, it has been suggested that S1P enhances the release of pro-inflammatory factors in microglia, thereby exacerbating ischemic stroke injury to some extent[74-75].Thus the role of S1P in ischemic stroke needs to be further explored and its role in the sequelae of psychiatric disorders in ischemic stroke has not yet been elucidated.

4.Prospect and Outlook

As the study of S1P in central nervous system disorders continues,it has been found that S1P does not act in the same way in different neurological disorders and that elevated levels of S1P in the brain may in some cases accelerate the progression of the disease.This may be due to the type of S1P receptor expressed on different neuronal cells, which may have very different effects in the disease.This “double-edged” nature of S1P in neurological disorders needs to be further explored.Other diseases of the central nervous system, such as epilepsy and brain tumors, are also associated with the sphingolipid metabolic pathway in which S1P is located[76-77].Because S1P has both the role of inhibiting neuronal apoptosis and promoting neuronal survival, as well as promoting the secretion of pro-inflammatory factors by glial cells, the role it plays in epilepsy has not been elucidated, and sphingolipid metabolism has been relatively little studied in epilepsy.Therefore, an indepth understanding of S1P-related signaling pathways and the key enzymes regulated by them is crucial for a clear understanding of CNS diseases, and elucidating their roles in different diseases and cells can provide a theoretical basis and technical support for the treatment of CNS diseases.