title: The Direct Effects of Fingolimod in the Central Nervous System: Implications for Relapsing Multiple Sclerosis.
abstract: Fingolimod, a structural analog of sphingosine derived from fungal metabolites, is a functional antagonist of the G-protein-coupled sphingosine 1-phosphate (S1P) receptors S1P(1,3,4,5). In the treatment of relapsing forms of multiple sclerosis (RMS), fingolimod acts by reversibly retaining central memory T cells and naïve T cells in lymph nodes, thereby reducing the recirculation of autoreactive lymphocytes to the central nervous system (CNS). Fingolimod also has differential effects on the trafficking and function of B-cell subtypes and natural killer (NK) cells in peripheral blood and the CNS. Fingolimod also crosses the blood-brain barrier (BBB) and accumulates in the CNS. Experimental evidence increasingly supports a direct action of fingolimod within the CNS on brain cells, providing protection against the neurodegenerative component of RMS. We review the direct influence of this compound on CNS pathogenesis in RMS, including the central effects of fingolimod in animal models of MS and on neural cell types that express S1P receptors, such as astrocytes, BBB endothelial cells, microglia, neurones, and oligodendrocytes, which are all involved in RMS pathology.
authors.affiliation: Advanced Neurosciences Institute, 101 Forrest Crossing Blvd, Suite 103, Franklin, TN, 37064-5430, USA. sfhunter@neurosci.us.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Hunter
authors.affiliation: Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, WA, USA. James.Bowen@swedish.org.
authors.forename: James D
authors.initials: JD
authors.lastname: Bowen
authors.affiliation: Department of Neurology, University of Chicago, Chicago, IL, USA. areder@neurology.bsd.uchicago.edu.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Reder
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology / Q000502:physiology
chemical_list: D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride