title: Multiple rodent models and behavioral measures reveal unexpected responses to FTY720 and DMF in experimental autoimmune encephalomyelitis.
abstract: Experimental autoimmune encephalomyelitis (EAE) is a widely-used rodent model for multiple sclerosis (MS), but a single model can hardly capture all features of MS. We investigated whether behavioral parameters in addition to clinical motor function scores could be used to assess treatment efficacy during score-free intervals in the relapsing-remitting EAE model in SJL/J mice. We studied the effects of the clinical reference compounds FTY720 (fingolimod, 0.5mg/kg/day) and dimethyl fumarate (DMF, 20-30 mg/kg/day) on clinical scores in several rodent EAE models in order to generate efficacy profiles. SJL/J mice with relapsing-remitting EAE were studied using behavioral tests, including rotarod, gait analysis, locomotor activity and grip strength. SJL/J mice were also examined according to Crawley's sociability and preference for social novelty test. Prophylactic treatment with FTY720 prevented clinical scores in three of the four EAE rodent models: Dark Agouti (DA) and Lewis rats and C57BL/6J mice. Neither prophylactic nor late-therapeutic treatment with FTY720 reduced clinical scores or reversed deficits in the rotarod test in SJL/J mice, but we observed effects on motor functions and sociability in the absence of clinical scores. Prophylactic treatment with FTY720 improved the gait of SJL/J mice whereas late-therapeutic treatment improved manifestations of reduced social (re)cognition or preference for social novelty. DMF was tested in three EAE models and did not improve clinical scores at the dose used. These data indicate that improvements in behavioral deficits can occur in absence of clinical scores, which indicate subtle drug effects and may have translational value for human MS.
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany. Electronic address: natasja.debruin@gmail.com.
authors.forename: N M W J
authors.initials: NM
authors.lastname: de Bruin
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Schmitz
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schiffmann
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Tafferner
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Jordan
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Häußler
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Tegeder
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany; Pharmazentrum Frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.
authors.forename: M J
authors.initials: MJ
authors.lastname: Parnham
mesh_terms: D000818:Animals; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D005684:Gait / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D011917:Rats, Inbred Lew; D021641:Recognition, Psychology / Q000187:drug effects; D012720:Severity of Illness Index; D012919:Social Behavior; D013995:Time
chemical_list: D007166:Immunosuppressive Agents; D000069462:Dimethyl Fumarate; D000068876:Fingolimod Hydrochloride
keywords: Experimental autoimmune encephalomyelitis; FTY720; Fumarate; Gait analysis; Multiple sclerosis; Social novelty test