期刊
EMBO MOLECULAR MEDICINE
卷 6, 期 11, 页码 1398-1422出版社
WILEY
DOI: 10.15252/emmm.201404168
关键词
endocannabinoids; multiple sclerosis; optic neuritis; pain; regulatory T cells
资金
- Landesoffensive fur Wissenschaftliche und Okonomische Exzellenz (LOEWE) Schwerpunkt 'Anwendungsorientierte Arzneimittelforschung'
- Deutsche Forschungsgemeinschaft [CRC1080 A9, SFB1039 A3]
- Else Kroner Fresenius Foundation (Translational Research Innovation Pharma (TRIP) graduate school, I.T.)
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.
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