RT Journal Article SR Electronic T1 S1P1 Receptor Modulation with Cyclical Recovery from Lymphopenia Ameliorates Mouse Model of Multiple Sclerosis JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.111.076109 DO 10.1124/mol.111.076109 A1 Pedro J Gonzalez-Cabrera A1 Stuart M Cahalan A1 Nhan Nguyen A1 Gor Sarkisyan A1 Nora B Leaf A1 Michael Cameron A1 Tomoyuki Kago A1 Hugh Rosen YR 2011 UL http://molpharm.aspetjournals.org/content/early/2011/10/26/mol.111.076109.abstract AB Multiple sclerosis therapies modulate T cell autoimmune pathology in the CNS but may exacerbate latent infections. Fingolimod, a non-selective S1P receptor agonist that induces sustained lymphopenia and accumulates in CNS represents a new modality of MS therapy. We hypothesized that sustained lymphopenia is not required for efficacy and that a selective, CNS-penetrant, but peripherally short-acting S1P1 agonist would show full efficacy in a mouse model of MS. Using daily treatment with 10 mg/kg CYM-5442, at onset of clinical signs in MOG35-55- induced EAE, we assessed clinical scores, CNS cellular infiltration, demyelination and gliosis for 12 days for CYM-5442, vehicle and fingolimod. CYM-5442 levels in CNS and plasma were determined at experiment termination and blood lymphopenia was measured at 3- and 24 h following last injection. Plasma levels of cytokines were assayed at protocol end. Changes in S1P1-eGFP expression on neurons and astrocytes during active EAE and upon CYM-5442 treatment were directly quantified by flow cytometry and Westerns using native-locus-eGFP tagged S1P1 mice. S1P1 agonism alone reduced pathology equivalent to fingolimod (maximally lymphopenic throughout) despite full reversal of lymphopenia within each dosing interval. CYM-5442 levels in CNS were sustained, but not in plasma. Neuronal and astrocytic S1P1 expression in EAE was suppressed by CYM-5442 treatment relative to vehicle mice, whereas key cytokine levels such as IL-17A were also significantly reduced in drug treated mice. S1P1-selective agonists inducing reversible lymphopenia while persisting in CNS may be effective MS treatments while limiting adverse consequences of long-term lymphopenia.