Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis

Musella, Alessandra; Gentile, Antonietta; Guadalupi, Livia; Rizzo, Francesca Romana; Vito, Francesca De; Fresegna, Diego; Bruno, Antonio; Dolcetti, Ettore; Vanni, Valentina; Vitiello, Laura; Bullitta, Silvia; Sanna, Krizia; Caioli, Silvia; Balletta, Sara; Nencini, Monica; Buttari, Fabio; Bassi, Mario Stampanoni; Centonze, Diego; Mandolesi, Georgia

doi:10.3390/cells9051290

Cited by 26 publications

(18 citation statements)

References 51 publications

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“…A recent study of ex vivo brain slice cultures from EAE mice and a Th1 cytokine-activated EAE-like microglial cell line suggests that ozanimod may also exert direct neuroprotective effects and attenuate local inflammatory responses [ 112 ]. Ozanimod treatment ameliorated EAE-driven striatal glutamatergic synapse alterations in an S1PR 1 -dependent manner and lowered the expression level of pro-inflammatory markers in EAE brain slices and microglial cell cultures [ 112 ].…”

Section: S1pr Modulation and Neuroprotection In Msmentioning

confidence: 99%

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Chun

Giovannoni

Hunter

2020

Drugs

146

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Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR 1 to S1PR 5 . Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. Electronic supplementary material The online version of this article (10.1007/s40265-020-01431-8) contains supplementary material, which is available to authorized users.

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Section: S1pr Modulation and Neuroprotection In Msmentioning

confidence: 99%

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Chun

Giovannoni

Hunter

2020

Drugs

146

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“…Ozanimod could dampen the EAE glutamatergic synaptic alterations by attenuating the local inflammatory response induced by the leading central nervous system (CNS) cellular actors of EAE synaptopathy (activated microglia and infiltrating T lymphocytes). 29 …”

Section: Ozanimodmentioning

confidence: 99%

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

Fronza

Lorefice

Frau

et al. 2021

DDDT

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Multiple sclerosis (MS) is a complex disease of the central nervous system that can cause permanent disability in young adults. A large armamentarium is available for its management and is increasing over time. Ozanimod is an oral drug belonging to the sphingosine-1-phosphate receptor (S1PR) modulator family recently approved in different countries for MS with active disease. It selectively modulates S1PR1 and S1PR5 to prevent autoreactive lymphocytes from entering the central nervous system (CNS), where they can determine inflammation and neurodegeneration. Ozanimod was tested in one Phase II and two Phase III pivotal trials and was shown to be effective and well tolerated. Moreover, further investigations, including comparative trials with other S1P modulators and MS disease-modifying drugs, are needed to better define placement in MS treatment. Furthermore, ozanimod is currently under evaluation for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, in international phase III studies. This article retraces the itinerary leading to the approval of ozanimod for MS treatment and its peculiarities and potentiality inside the S1PR modulator family.

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“…The authors highlighted that pro-regenerative EVs, obtained by incubation of activated microglia with IL-4 and MSCs, contained high levels of anandamide and sphingosine 1 phosphate (S1P), two lipids that together with the protein Wnt3a share a key chemoattractant function for OPCs [ 36 ] ( Figure 3 a,b). The relevance of S1P derived also by the evidence of a beneficial effect on remyelination mediated by S1PR modulators, a group of drugs used in the MS therapy [ 36 , 89 ] ( Figure 3 c). It emerged also the role of A1-astrocytes in mediating the anti-remyelinating EVs effects on OPCs.…”

Section: Potential Involvement Of Evs In Remyelinating Processesmentioning

confidence: 99%

Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis

Dolcetti

Bruno

Guadalupi

et al. 2020

IJMS

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Extracellular vesicles (EVs) represent a new reality for many physiological and pathological functions as an alternative mode of intercellular communication. This is due to their capacity to interact with distant recipient cells, usually involving delivery of the EVs contents into the target cells. Intensive investigation has targeted the role of EVs in different pathological conditions, including multiple sclerosis (MS). MS is a chronic inflammatory and neurodegenerative disease of the nervous system, one of the main causes of neurological disability in young adults. The fine interplay between the immune and nervous systems is profoundly altered in this disease, and EVs seems to have a relevant impact on MS pathogenesis. Here, we provide an overview of both clinical and preclinical studies showing that EVs released from blood–brain barrier (BBB) endothelial cells, platelets, leukocytes, myeloid cells, astrocytes, and oligodendrocytes are involved in the pathogenesis of MS and of its rodent model experimental autoimmune encephalomyelitis (EAE). Most of the information points to an impact of EVs on BBB damage, on spreading pro-inflammatory signals, and altering neuronal functions, but EVs reparative function of brain damage deserves attention. Finally, we will describe recent advances about EVs as potential therapeutic targets and tools for therapeutic intervention in MS.

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Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis

Cited by 26 publications

References 51 publications

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

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

Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis

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