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Fingolimod provides long‐term protection in rodent models of cerebral ischemia
Author(s) -
Wei Ying,
Yemisci Muge,
Kim HyungHwan,
Yung Lai Ming,
Shin Hwa Kyoung,
Hwang SeoKyoung,
Guo Shuzhen,
Qin Tao,
Alsharif Nafiseh,
Brinkmann Volker,
Liao James K,
Lo Eng H,
Waeber Christian
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22186
Subject(s) - fingolimod , neuroprotection , medicine , microglia , pharmacology , ischemia , excitotoxicity , inflammation , stroke (engine) , anesthesia , multiple sclerosis , neuroscience , immunology , receptor , glutamate receptor , biology , mechanical engineering , engineering
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