R‐flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice

EMBO Molecular Medicine

Katja Schmitz²  Natasja de Bruin³  Philipp Bishay²  Julia Männich²  Annett Häussler²  Christine Altmann²  Nerea Ferreirós²  Jörn Lötsch²  Alfred Ultsch¹  Michael J Parnham³  Gerd Geisslinger² 

[1]DataBionics Research Group, University of Marburg, Marburg, Germany

[2]Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt am Main, Germany

[3]Fraunhofer Institute of Molecular Biology and Applied Ecology, Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, Germany

关键词: endocannabinoids;    multiple sclerosis;    optic neuritis;    pain;    regulatory T cells;   

DOI  :  10.15252/emmm.201404168

来源: Wiley

【 摘 要 】

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.

Synopsis

R-flurbiprofen treatment of experimental autoimmune encephalomyelitis in mouse models of multiple sclerosis prevented and attenuated relapsing-remitting and primary progressive EAE, suggesting that R-flurbiprofen could restore motor functions and alleviate MS-associated chronic pain in humans.

• R-flurbiprofen favored regulatory and inflammation-resolving immune cells and reduced myelin and axon destruction
• R-flurbiprofen increased anti-inflammatory endocannabinoids in the periphery and central nervous system and reduced pro-inflammatory lipid signaling molecules
• Effects are likely mediated through a multi-targeted reduction of pro-inflammatory gene transcription, anti-oxidative neuroprotection and favoring of inflammation-resolving lipid signaling molecules

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.