title: R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice.
abstract: R-flurbiprofen is the non-cyclooxygenase inhibiting R-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen, which was assessed as a remedy for Alzheimer's disease. Because of its anti-inflammatory, endocannabinoid-modulating and antioxidative properties, combined with low toxicity, the present study assessed R-flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. Oral R-flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing-remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R-flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE-evoked hyperalgesia. R-flurbiprofen treatment increased CD4(+)CD25(+)FoxP3(+) regulatory T cells, CTLA4(+) inhibitory T cells and interleukin-10, whereas the EAE-evoked upregulation of pro-inflammatory genes in the spinal cord was strongly reduced. The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R to S inversion. The promising results suggest potential efficacy of R-flurbiprofen in human MS, and its low toxicity may justify a clinical trial.
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Schmitz
authors.affiliation: Fraunhofer Institute of Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, Germany.
authors.forename: Natasja
authors.initials: N
authors.lastname: de Bruin
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Bishay
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Männich
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Altmann
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany Fraunhofer Institute of Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Lötsch
authors.affiliation: DataBionics Research Group, University of Marburg, Marburg, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Ultsch
authors.affiliation: Fraunhofer Institute of Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, Germany.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parnham
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany Fraunhofer Institute of Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Institute of Clinical Pharmacology Goethe-University Hospital, Frankfurt am Main, Germany Fraunhofer Institute of Molecular Biology and Applied Ecology Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, Germany tegeder@em.uni-frankfurt.de.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D063388:Endocannabinoids / Q000097:blood; D005260:Female; D005480:Flurbiprofen / Q000627:therapeutic use*; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009900:Optic Nerve / Q000473:pathology; D011453:Prostaglandins / Q000134:cerebrospinal fluid; D013116:Spinal Cord / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D063388:Endocannabinoids; D011453:Prostaglandins; D005480:Flurbiprofen
keywords: endocannabinoids; multiple sclerosis; optic neuritis; pain; regulatory T cells