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Drug Design, Development and Therapy (submit here)

This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the design and development of drugs, as well as the clinical outcomes, patient safety, and programs targeted at the effective and safe use of medicines. Sign up for email alerts here.

88,007 Monthly downloads/views I 4.319 Impact Factor I 6.6 CiteScore I 1.12 Source Normalized Impact per Paper (SNIP) I 0.784 Scimago Journal & Country Rank (SJR)

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Molecular pharmacodynamics of new oral drugs used in the treatment of multiple sclerosis

Author(s): Luigi Di Nuzzo, Rosamaria Orlando, Carla Nasca, Ferdinando Nicoletti

Publication date: 2014-05-19

Journal: Drug Design, Development and Therapy

Publisher: Dove Medical Press

Keywords: demyelinating diseases, pharmacotherapy, fingolimod, dimethyl fumarate, laquinimod, teriflunomide

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Abstract

New oral drugs have considerably enriched the therapeutic armamentarium for the treatment of multiple sclerosis. This review focuses on the molecular pharmacodynamics of fingolimod, dimethyl fumarate (BG-12), laquinimod, and teriflunomide. We specifically comment on the action of these drugs at three levels: 1) the regulation of the immune system; 2) the permeability of the blood–brain barrier; and 3) the central nervous system. Fingolimod phosphate (the active metabolite of fingolimod) has a unique mechanism of action and represents the first ligand of G-protein-coupled receptors (sphingosine-1-phosphate receptors) active in the treatment of multiple sclerosis. Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-related factor 2 pathway of cell defense as a result of an initial depletion of reduced glutathione. We discuss how this mechanism lies on the border between cell protection and toxicity. Laquinimod has multiple (but less defined) mechanisms of action, which make the drug slightly more effective on disability progression than on annualized relapse rate in clinical studies. Teriflunomide acts as a specific inhibitor of the de novo pyrimidine biosynthesis. We also discuss new unexpected mechanisms of these drugs, such as the induction of brain-derived neurotrophic factor by fingolimod and the possibility that laquinimod and teriflunomide regulate the kynurenine pathway of tryptophan metabolism.

Most cited references 91

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Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

Mehrdad Matloubian, Charles G. Lo, Guy Cinamon … (2004)

Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.

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Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs.

Jason G. Cyster, Susan Schwab (2012)

Much has been learned about how cells enter lymphoid tissues. But how do they leave? Sphingosine-1-phosphate (S1P) has emerged over the past decade as a central mediator of lymphocyte egress. In this review, we summarize the current understanding of how S1P promotes exit from the secondary lymphoid organs and thymus. We review what is known about additional requirements for emigration and summarize the mostly distinct requirements for exit from the bone marrow. Egress from lymphoid organs is limited during immune responses, and we examine how this regulation works. There is accumulating evidence for roles of S1P in directing immune cell behavior within lymphoid tissues. How such actions can fit together with the egress-promoting role of S1P is discussed. Finally, we examine current understanding of how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression.

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The alliance of sphingosine-1-phosphate and its receptors in immunity.

Juan Rivera, Richard Proia, Ana Olivera (2008)

Sphingosine-1-phosphate (S1P) is a biologically active metabolite of plasma-membrane sphingolipids that is essential for immune-cell trafficking. Its concentration is increased in many inflammatory conditions, such as asthma and autoimmunity. Much of the immune function of S1P results from the engagement of a family of G-protein-coupled receptors (S1PR1-S1PR5). Recent findings on the role of S1P in immunosurveillance, the discovery of regulatory mechanisms in S1P-mediated immune-cell trafficking and new advances in understanding the mechanism by which S1P affects immune-cell function indicate that the alliance between S1P and its receptors has a fundamental role in immunity.