PT  - JOURNAL ARTICLE
AU  - Pedro J. Gonzalez-Cabrera
AU  - Stuart M. Cahalan
AU  - Nhan Nguyen
AU  - Gor Sarkisyan
AU  - Nora B. Leaf
AU  - Michael D. Cameron
AU  - Tomoyuki Kago
AU  - Hugh Rosen
TI  - S1P<sub>1</sub> Receptor Modulation with Cyclical Recovery from Lymphopenia Ameliorates Mouse Model of Multiple Sclerosis
AID  - 10.1124/mol.111.076109
DP  - 2012 Feb 01
TA  - Molecular Pharmacology
PG  - 166--174
VI  - 81
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/81/2/166.short
4100  - http://molpharm.aspetjournals.org/content/81/2/166.full
SO  - Mol Pharmacol2012 Feb 01; 81
AB  - Multiple sclerosis (MS) therapies modulate T-cell autoimmunity in the central nervous system (CNS) but may exacerbate latent infections. Fingolimod, a nonselective sphingosine-1-phosphate (S1P) receptor agonist that induces sustained lymphopenia and accumulates in the CNS, represents a new treatment modality for MS. We hypothesized that sustained lymphopenia would not be required for efficacy and that a selective, CNS-penetrant, peripherally short-acting, S1P1 agonist would show full efficacy in a mouse MS model. Using daily treatment with 10 mg/kg 2-(4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl amino)ethanol (CYM-5442) at the onset of clinical signs in myelin oligodendrocyte glycoprotein MOG35–55- induced experimental allergic encephalomyelitis (EAE), we assessed clinical scores, CNS cellular infiltration, demyelination, and gliosis for 12 days with CYM-5442, vehicle, or fingolimod. CYM-5442 levels in CNS and plasma were determined at experiment termination, and blood lymphopenia was measured 3 and 24 h after the last injection. Plasma levels of cytokines were assayed at the end of the protocol. Changes in S1P1-enhanced green fluorescent protein expression on neurons and astrocytes during active EAE and upon CYM-5442 treatment were quantified with flow cytometry and Western blotting by using native-locus enhanced green fluorescent protein-tagged S1P1 mice. S1P1 agonism alone reduced pathological features as did fingolimod (maximally lymphopenic throughout), despite full reversal of lymphopenia within each dosing interval. CYM-5442 levels in CNS but not in plasma were sustained. Neuronal and astrocytic S1P1 expression in EAE was suppressed by CYM-5442 treatment, relative to vehicle, and levels of key cytokines, such as interleukin 17A, were also significantly reduced in drug-treated mice. S1P1-selective agonists that induce reversible lymphopenia while persisting in the CNS may be effective MS treatments.