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

Annals of Neurology - Tập 69 Số 1 - Trang 119-129 - 2011
Ying Wei1, Müge Yemişçi1, Hyung‐Hwan Kim2,3, Lai‐Ming Yung1, Hwa Kyoung Shin1, Seo‐Kyoung Hwang2, Shuzhen Guo1, Tao Qin1, Nafiseh Alsharif1, Volker Brinkmann4, James K. Liao2, Eng H. Lo1, Christian Waeber1
1Department of Radiology, Massachusetts General Hospital, Charlestown, MA
2Department of Vascular Medicine Research, Brigham & Women's Hospital, Cambridge, MA
3International Research Center of Bioscience & Biotechnology, Jungwon University, Goesan, Korea
4Novartis Institutes for Biomedical Research, Autoimmunity, Transplantation and Inflammation, Basel, Switzerland

Tóm tắt

AbstractObjective: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

Từ khóa


Tài liệu tham khảo

10.1016/S0166-2236(99)01401-0

10.1038/nrm2329

10.1006/jmcc.2001.1429

10.1152/ajpheart.01029.2001

10.1016/0960-894X(95)00127-F

10.1074/jbc.C200176200

10.1097/00007890-200209150-00004

10.1056/NEJMoa0909494

10.1056/NEJMoa0907839

10.1111/j.1600-6143.2004.00642.x

10.1211/0022357991777065

10.1016/j.transproceed.2007.04.027

10.1097/01.tp.0000269794.74990.da

10.1016/j.transproceed.2006.12.010

10.1152/ajprenal.00311.2005

Kim H‐H, 2008, The sphingosine‐1‐phosphate analogue FTY720 is neuroprotective in a rodent model of brain ischemia., Stroke, 39, 729

10.1097/00004647-199705000-00005

10.1016/0304-3940(95)11752-I

10.1161/STROKEAHA.108.524504

10.1016/S0165-5728(00)00285-X

10.1038/sj.jcbfm.9600406

10.1161/01.STR.26.7.1252

10.1152/physrev.1999.79.4.1431

10.1007/BF02815139

10.1046/j.1471-4159.2003.02219.x

10.1038/sj.jcbfm.9600258

10.1161/01.STR.30.12.2752

10.1016/j.pharmthera.2007.08.005

10.1097/CCM.0b013e3181aa5de1

10.1111/j.1471-4159.2009.06202.x

10.1001/archneur.58.4.669

10.1179/174313208X341085

10.1074/jbc.M306896200

10.1038/nature02284

10.1084/jem.20091619

Kataoka H, 2005, FTY720, sphingosine 1‐phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration, Cell Mol Immunol, 2, 439

10.1007/s11605-009-1104-3

10.1016/j.transproceed.2004.12.280

10.1161/CIRCULATIONAHA.105.593046

10.1016/j.neuroscience.2009.10.067

DingK BlondeauN LaiC et al.Neuron‐derived sphingosine‐1‐phosphate protects brain endothelial cells from ischemia‐induced cell death via Akt‐mediated mechanisms. Program No. 199.111. 34th Society for Neuroscience Meeting San Diego 2004.

10.1016/j.bbrc.2009.08.142

10.1161/STROKEAHA.109.568899

10.1073/pnas.95.18.10960

10.1016/j.brainres.2006.02.080

10.1097/00004647-199911000-00005

10.1038/jcbfm.2008.88

10.1161/STROKEAHA.108.536680

10.1002/ana.20602

Thông tin
Thông tin xuất bản

Annals of Neurology

Tập 69 Số 1

119-129

Thông tin tác giả