Fingolimod provides long-term protection in rodent models of cerebral ischemia
Ying Wei MD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorMuge Yemisci MD, PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorHyung-Hwan Kim PhD
Department of Vascular Medicine Research, Brigham & Women's Hospital, Cambridge, MA
International Research Center of Bioscience & Biotechnology, Jungwon University, Goesan, Korea
Search for more papers by this authorLai Ming Yung PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorHwa Kyoung Shin PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorSeo-Kyoung Hwang MS
Department of Vascular Medicine Research, Brigham & Women's Hospital, Cambridge, MA
Search for more papers by this authorShuzhen Guo PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorTao Qin
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorNafiseh Alsharif
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorVolker Brinkmann PhD
Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland
Search for more papers by this authorJames K Liao MD
Department of Vascular Medicine Research, Brigham & Women's Hospital, Cambridge, MA
Search for more papers by this authorEng H Lo PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorCorresponding Author
Christian Waeber PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Massachusetts General Hospital, CNY149 Room 6403, 149 13th Street, Charlestown, MA 02129Search for more papers by this authorYing Wei MD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorMuge Yemisci MD, PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorHyung-Hwan Kim PhD
Department of Vascular Medicine Research, Brigham & Women's Hospital, Cambridge, MA
International Research Center of Bioscience & Biotechnology, Jungwon University, Goesan, Korea
Search for more papers by this authorLai Ming Yung PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorHwa Kyoung Shin PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorSeo-Kyoung Hwang MS
Department of Vascular Medicine Research, Brigham & Women's Hospital, Cambridge, MA
Search for more papers by this authorShuzhen Guo PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorTao Qin
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorNafiseh Alsharif
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorVolker Brinkmann PhD
Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland
Search for more papers by this authorJames K Liao MD
Department of Vascular Medicine Research, Brigham & Women's Hospital, Cambridge, MA
Search for more papers by this authorEng H Lo PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Search for more papers by this authorCorresponding Author
Christian Waeber PhD
Department of Radiology, Massachusetts General Hospital, Charlestown, MA
Massachusetts General Hospital, CNY149 Room 6403, 149 13th Street, Charlestown, MA 02129Search for more papers by this authorAbstract
Objective:
The sphingosine-1-phosphate (S1P) receptor agonist fingolimod (FTY720), that has shown efficacy in advanced multiple sclerosis clinical trials, decreases reperfusion injury in heart, liver, and kidney. We therefore tested the therapeutic effects of fingolimod in several rodent models of focal cerebral ischemia. To assess the translational significance of these findings, we asked whether fingolimod improved long-term behavioral outcomes, whether delayed treatment was still effective, and whether neuroprotection can be obtained in a second species.
Methods:
We used rodent models of middle cerebral artery occlusion and cell-culture models of neurotoxicity and inflammation to examine the therapeutic potential and mechanisms of neuroprotection by fingolimod.
Results:
In a transient mouse model, fingolimod reduced infarct size, neurological deficit, edema, and the number of dying cells in the core and periinfarct area. Neuroprotection was accompanied by decreased inflammation, as fingolimod-treated mice had fewer activated neutrophils, microglia/macrophages, and intercellular adhesion molecule-1 (ICAM-1)-positive blood vessels. Fingolimod-treated mice showed a smaller infarct and performed better in behavioral tests up to 15 days after ischemia. Reduced infarct was observed in a permanent model even when mice were treated 4 hours after ischemic onset. Fingolimod also decreased infarct size in a rat model of focal ischemia. Fingolimod did not protect primary neurons against glutamate excitotoxicity or hydrogen peroxide, but decreased ICAM-1 expression in brain endothelial cells stimulated by tumor necrosis factor alpha.
Interpretation:
These findings suggest that anti-inflammatory mechanisms, and possibly vasculoprotection, rather than direct effects on neurons, underlie the beneficial effects of fingolimod after stroke. S1P receptors are a highly promising target in stroke treatment. ANN NEUROL, 2010
Supporting Information
Additional supporting information can be found in the online version of this article.
| Filename | Description |
|---|---|
| ANA_22186_sm_suppinfofig1.tif4.5 MB | Supporting Figure 1 |
| ANA_22186_sm_suppinfofig2.tif5.2 MB | Supporting Figure 2 |
| ANA_22186_sm_suppinfofig3.tif1 MB | Supporting Figure 3 |
| ANA_22186_sm_suppinfofig4.tif2.6 MB | Supporting Figure 4 |
| ANA_22186_sm_suppinfofig5.tif10.2 MB | Supporting Figure 5 |
| ANA_22186_sm_suppinfo.doc50.5 KB | Supporting Information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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