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FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage.
Brain Pathol. 2009 Apr; 19(2):254-66.BP

Abstract

FTY720 (fingolimod) is an oral sphingosine-1 phosphate (S1P) receptor modulator in phase III development for the treatment of multiple sclerosis. To further investigate its mode of action, we analyzed gene expression in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). FTY720 downregulated inflammatory genes in addition to vascular adhesion molecules. It decreased the matrix metalloproteinase gene MMP-9 and increased its counterregulator--tissue inhibitor of metalloproteinase, TIMP-1--resulting in a proteolytic balance that favors preservation of blood-brain-barrier (BBB) integrity. Furthermore, FTY720 reduced S1P lyase that increases the S1P concentration in the brain, in line with a marked reversal of neurological deficits and raising the possibility for enhanced triggering of S1P receptors on resident brain cells. This is accompanied by an increase in S1P(1) and S1P(5) in contrast with the attenuation of S1P(3) and S1P(4). Late-stage rescue therapy with FTY720, even up to 1 month after EAE onset, reversed BBB leakiness and reduced demyelination, along with normalization of neurologic function. Our results indicate rapid blockade of ongoing disease processes by FTY720, and structural restoration of the CNS parenchyma, which is likely caused by the inhibition of autoimmune T cell infiltration and direct modulation of microvascular and/or glial cells.

Authors+Show Affiliations

Novartis Institutes for BioMedical Research, Brunner Strasse 59, Vienna, Austria. carolyn.foster@novartis.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18540945

Citation

Foster, Carolyn A., et al. "FTY720 Rescue Therapy in the Dark Agouti Rat Model of Experimental Autoimmune Encephalomyelitis: Expression of Central Nervous System Genes and Reversal of Blood-brain-barrier Damage." Brain Pathology (Zurich, Switzerland), vol. 19, no. 2, 2009, pp. 254-66.
Foster CA, Mechtcheriakova D, Storch MK, et al. FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain Pathol. 2009;19(2):254-66.
Foster, C. A., Mechtcheriakova, D., Storch, M. K., Balatoni, B., Howard, L. M., Bornancin, F., Wlachos, A., Sobanov, J., Kinnunen, A., & Baumruker, T. (2009). FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain Pathology (Zurich, Switzerland), 19(2), 254-66. https://doi.org/10.1111/j.1750-3639.2008.00182.x
Foster CA, et al. FTY720 Rescue Therapy in the Dark Agouti Rat Model of Experimental Autoimmune Encephalomyelitis: Expression of Central Nervous System Genes and Reversal of Blood-brain-barrier Damage. Brain Pathol. 2009;19(2):254-66. PubMed PMID: 18540945.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. AU - Foster,Carolyn A, AU - Mechtcheriakova,Diana, AU - Storch,Maria K, AU - Balatoni,Balázs, AU - Howard,Laurence M, AU - Bornancin,Frédéric, AU - Wlachos,Alexander, AU - Sobanov,Jury, AU - Kinnunen,Anu, AU - Baumruker,Thomas, Y1 - 2008/06/04/ PY - 2008/6/11/pubmed PY - 2009/5/2/medline PY - 2008/6/11/entrez SP - 254 EP - 66 JF - Brain pathology (Zurich, Switzerland) JO - Brain Pathol VL - 19 IS - 2 N2 - FTY720 (fingolimod) is an oral sphingosine-1 phosphate (S1P) receptor modulator in phase III development for the treatment of multiple sclerosis. To further investigate its mode of action, we analyzed gene expression in the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE). FTY720 downregulated inflammatory genes in addition to vascular adhesion molecules. It decreased the matrix metalloproteinase gene MMP-9 and increased its counterregulator--tissue inhibitor of metalloproteinase, TIMP-1--resulting in a proteolytic balance that favors preservation of blood-brain-barrier (BBB) integrity. Furthermore, FTY720 reduced S1P lyase that increases the S1P concentration in the brain, in line with a marked reversal of neurological deficits and raising the possibility for enhanced triggering of S1P receptors on resident brain cells. This is accompanied by an increase in S1P(1) and S1P(5) in contrast with the attenuation of S1P(3) and S1P(4). Late-stage rescue therapy with FTY720, even up to 1 month after EAE onset, reversed BBB leakiness and reduced demyelination, along with normalization of neurologic function. Our results indicate rapid blockade of ongoing disease processes by FTY720, and structural restoration of the CNS parenchyma, which is likely caused by the inhibition of autoimmune T cell infiltration and direct modulation of microvascular and/or glial cells. SN - 1750-3639 UR - https://www.unboundmedicine.com/medline/citation/18540945/FTY720_rescue_therapy_in_the_dark_agouti_rat_model_of_experimental_autoimmune_encephalomyelitis:_expression_of_central_nervous_system_genes_and_reversal_of_blood_brain_barrier_damage_ L2 - https://doi.org/10.1111/j.1750-3639.2008.00182.x DB - PRIME DP - Unbound Medicine ER -