| Anti-inflammatory effects of FTY720 do not prevent neuronal cell loss in a rat model of optic neuritis. | |
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MedLine Citation:
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PMID: 21406175 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In multiple sclerosis, long-term disability is caused by axonal and neuronal damage. Established therapies target primarily the inflammatory component of the disease, but fail to prevent neurodegeneration. Fingolimod (codenamed FTY720) is an oral sphingosine 1-phosphate (S1P) receptor modulator with promising results in phase II trials in multiple sclerosis patients and is under further development as a novel treatment for multiple sclerosis. To evaluate whether FTY720 has neuroprotective properties, we tested this drug in a rat model of myelin oligodendrocyte glycoprotein-induced optic neuritis. FTY720 exerted significant anti-inflammatory effects during optic neuritis and reduced inflammation, demyelination, and axonal damage; however, FTY720 treatment did not prevent apoptosis of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. Consistent with this lack of effect on RGC survival, FTY720 treatment did not improve visual function, nor did it prevent apoptosis of RGCs in vitro. We observed a persistent activation of apoptotic signaling pathways in RGCs under FTY720 treatment, a possible underlying mechanism for the lack of neuroprotection in the presence of strong anti-inflammatory effects, Furthermore, FTY720 shifted the remaining inflammation in the optic nerve toward neurotoxicity by modest up-regulation of potential neurotoxic cytokines. We conclude that FTY720-induced anti-inflammation and axon protection did not of itself protect neurons from apoptotic cell death. |
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Authors:
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Christian R Rau; Katharina Hein; Muriel B Sättler; Benedikt Kretzschmar; Carina Hillgruber; Bradford L McRae; Ricarda Diem; Mathias Bähr |
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Publication Detail:
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Type: Journal Article Date: 2011-02-26 |
Journal Detail:
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Title: The American journal of pathology Volume: 178 ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-03-25 Completed Date: 2011-07-15 Revised Date: 2012-04-02 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 1770-81 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Neurology, University Medicine Göttingen, Göttingen, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Inflammatory Agents / pharmacology* Apoptosis Cytokines / metabolism Disease Models, Animal Electrophysiology / methods Encephalomyelitis, Autoimmune, Experimental / immunology Female Glycoproteins / metabolism Immunosuppressive Agents / pharmacology Myelin Sheath / metabolism Neurons / cytology* Oligodendroglia / metabolism Optic Neuritis / metabolism* Propylene Glycols / pharmacology* Rats Sphingosine / analogs & derivatives*, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents; 0/Cytokines; 0/Glycoproteins; 0/Immunosuppressive Agents; 0/Propylene Glycols; 123-78-4/Sphingosine; 162359-55-9/fingolimod |
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