Multiple sclerosis (MS) is a neurological disease that leads to severe physical and cognitive disabilities. Drugs used in the treatment of MS vary from small synthetic molecules to large macromolecules such as antibodies. Sphingosine 1-phosphate receptor modulators are frequently used for the treatment of MS. These medicines prevent the egress of lymphocytes from secondary lymphoid organs leading to immune system suppression. Currently, four S1PR modulators are on the market and several potential drug candidates are in clinical trials for the treatment of MS. These compounds differ in chemical structure, adverse effects, and efficacy points of view. The current article reviews the latest studies on S1PR1 modulators and compares them with other MS drugs in terms of efficacy, tolerability, and safety. A special focus was dedicated to discussing the structure-activity relationships of these compounds and performing a three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis to gain better insight into the ligand-receptor interaction mode.
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Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington's disease.
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Translational Neurodegeneration Research and Neuropathology Lab, Department of Clinical Medicine (KlinMed), Medical Faculty, University of Oslo (UiO) and Section of Neuropathology Research, Department of Pathology, Clinics for Laboratory Medicine (KLM), Oslo University Hospital (OUS), Sognsvannsveien 20, Oslo N-0372, Norway; Institute of Nutritional Medicine (INUM) and Lübeck Institute of Dermatology (LIED), University of Lübeck (UzL) and University Medical Center Schleswig-Holstein (UKSH), Ratzeburger Allee 160, Lübeck D-23538, Germany; Department of Neuromedicine and Neuroscience, Faculty of Medicine and Life Sciences, University of Latvia (LU), Jelgavas iela 3, Rīga LV-1004, Latvia; Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The Georg S. Wise Faculty of Life Sciences, Tel Aviv University (TAU), Ramat Aviv IL-6997801, Israel. Electronic address:
Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators. Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions.
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Experimental Medicine Division, Department of Medicine, McGill University, Montréal, QC, Canada.
Study Question: What role do sphingolipids have in mediating human sperm capacitation?
Summary Answer: Sphingosine 1-phosphate (S1P) mediates the acquisition of fertilizing competency in human spermatozoa by engaging with its Gi-coupled receptor S1PR1 and promoting production of reactive oxygen species such as nitric oxide and superoxide anion.
What Is Known Already: Bioactive sphingolipids, such as S1P, are fundamental for regulating numerous physiological domains and processes, such as cell membranes and signalling, cell death and proliferation, cell migration and invasiveness, inflammation, and central nervous system development.
Study Design, Size, Duration: Semen samples were obtained from a cohort of 10 healthy non-smoking volunteers (18-30 years old) to investigate the role of S1P in sperm.
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Institute for Molecular Medicine, MSH Medical School Hamburg, Hamburg, Germany.
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