Fingolimod provides long-term protection in rodent models of cerebral ischemia

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 f...

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Bibliographic Details
Published in:Annals of neurology 2011-01, Vol.69 (1), p.119-129
Main Authors: Wei, Ying, Yemisci, Muge, Kim, Hyung-Hwan, Yung, Lai Ming, Shin, Hwa Kyoung, Hwang, Seo-Kyoung, Guo, Shuzhen, Qin, Tao, Alsharif, Nafiseh, Brinkmann, Volker, Liao, James K, Lo, Eng H, Waeber, Christian
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Biological and medical sciences
Brain Ischemia - drug therapy
Brain Ischemia - prevention & control
Disease Models, Animal
Fingolimod Hydrochloride
Immunosuppressive Agents - therapeutic use
In Vitro Techniques
Inflammation - drug therapy
Ischemia
Medical research
Medical sciences
Mice
Mice, Inbred C57BL
Neurology
Neurons - drug effects
Neurons - immunology
Neuroprotective Agents - pharmacology
Neuroprotective Agents - therapeutic use
Neurotoxicity Syndromes - prevention & control
Propylene Glycols - pharmacology
Propylene Glycols - therapeutic use
Rats
Receptors, Lysosphingolipid - agonists
Rodents
Sphingosine - analogs & derivatives
Sphingosine - pharmacology
Sphingosine - therapeutic use
Stroke - drug therapy
Stroke - prevention & control
Vascular diseases and vascular malformations of the nervous system
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Summary: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
ISSN:0364-5134
1531-8249
DOI:10.1002/ana.22186