• Chuan Qin, Wen-Hui Fan, Qian Liu, Ke Shang, Madhuvika Murugan, Long-Jun Wu, Wei Wang, and Dai-Shi Tian.
• From the Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (C.Q., W.-H.F., Q.L., K.S., W.W., D.-S.T.); Department of Neurology, General Hospital of the Yangtze River Shipping, Wuhan, China (W.-H.F.); Department of Neurology, Mayo Clinic, Rochester, MN (M.M., L.-J.W.); and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (M.M., L.-J.W.).
• Stroke. 2017 Dec 1; 48 (12): 3336-3346.

Background And PurposeWhite matter (WM) ischemic injury, a major neuropathological feature of cerebral small vessel diseases, is an important cause of vascular cognitive impairment in later life. The pathogenesis of demyelination after WM ischemic damage are often accompanied by microglial activation. Fingolimod (FTY720) was approved for the treatment of multiple sclerosis for its immunosuppression property. In this study, we evaluated the neuroprotective potential of FTY720 in a WM ischemia model.MethodsChronic WM ischemic injury model was induced by bilateral carotid artery stenosis. Cognitive function, WM integrity, microglial activation, and potential pathway involved in microglial polarization were assessed after bilateral carotid artery stenosis.ResultsDisruption of WM integrity was characterized by demyelination in the corpus callosum and disorganization of Ranvier nodes using Luxol fast blue staining, immunofluorescence staining, and electron microscopy. In addition, radial maze test demonstrated that working memory performance was decreased at 1-month post-bilateral carotid artery stenosis-induced injury. Interestingly, FTY720 could reduce cognitive decline and ameliorate the disruption of WM integrity. Mechanistically, cerebral hypoperfusion induced microglial activation, production of associated proinflammatory cytokines, and priming of microglial polarization toward the M1 phenotype, whereas FTY720 attenuated microglia-mediated neuroinflammation after WM ischemia and promoted oligodendrocytogenesis by shifting microglia toward M2 polarization. FTY720's effect on microglial M2 polarization was largely suppressed by selective signal transducer and activator of transcription 3 (STAT3) blockade in vitro, revealing that FTY720-enabled shift of microglia from M1 to M2 polarization state was possibly mediated by STAT3 signaling.ConclusionsOur study suggested that FTY720 might be a potential therapeutic drug targeting brain inflammation by skewing microglia toward M2 polarization after chronic cerebral hypoperfusion.© 2017 American Heart Association, Inc.

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