Fingolimod provides long-term protection in rodent models of cerebral ischemia
Article first published online: 12 NOV 2010
Copyright © 2010 American Neurological Association
Annals of Neurology
Volume 69, Issue 1, pages 119–129, January 2011
How to Cite
Wei, Y., Yemisci, M., Kim, H.-H., Yung, L. M., Shin, H. K., Hwang, S.-K., Guo, S., Qin, T., Alsharif, N., Brinkmann, V., Liao, J. K., Lo, E. H. and Waeber, C. (2011), Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann Neurol., 69: 119–129. doi: 10.1002/ana.22186
- Issue published online: 28 JAN 2011
- Article first published online: 12 NOV 2010
- Manuscript Accepted: 30 JUL 2010
- Manuscript Revised: 30 JUN 2010
- Manuscript Received: 29 MAR 2010
- National Institute of Neurological Disorders and Stroke. Grant Numbers: R01NS049263, P01NS55104, R37NS37074, R01NS53560
- National Heart, Lung and Blood Institute. Grant Number: HL052233
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.
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.
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.
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