Effect of fingolimod on oligodendrocyte maturation under prolonged cerebral hypoperfusion

• Published in: Brain research 2019-10, Vol.1720, p.146294-146294, Article 146294
• Main Authors: Yasuda, Ken, Maki, Takakuni, Saito, Satoshi, Yamamoto, Yumi, Kinoshita, Hisanori, Choi, Yoon Kyung, Arumugam, Thiruma Valavan, Lim, Yun-An, Chen, Christopher Li Hsian, Wong, Peter Tsun-Hon, Ihara, Masafumi, Takahashi, Ryosuke
• Format: Article
• Language: English
• Subjects: Fingolimod; FTY720; Oligodendrocyte; Oligodendrocyte precursor cell; Subcortical ischemic vascular dementia
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2019.06.013

•Fingolimod rescues ischemia-induced suppression of oligodendrocyte differentiation.•Fingolimod promotes oligodendrogenesis under prolonged cerebral hypoperfusion in mice.•Fingolimod may be a therapeutic candidate for subcortical ischemic vascular dementia. Oligodendrocytes (OLGs) support neuronal system and have crucial roles for brain homeostasis. As the renewal and regeneration of OLGs derived from oligodendrocyte precursor cells (OPCs) are inhibited by various pathological conditions, the restoration of impaired oligodendrogenesis is a therapeutic strategy for OLG-related diseases such as subcortical ischemic vascular dementia (SIVD). Fingolimod (FTY720), a drug for multiple sclerosis, is reported to elicit a cytoprotective effect on OPCs in vitro. However, the effects of fingolimod against ischemia-induced suppression of OPC differentiation remain unknown. Hence, the purpose of this study was to investigate the effectiveness of fingolimod against ischemia-induced suppression of oligodendrogenesis. For the in vitro experiments, primary rat cultured OPCs were incubated with a non-lethal concentration of CoCl2 to induce chemical hypoxic conditions and were treated with or without fingolimod-phosphate. We found that low concentration fingolimod-phosphate directly rescued ischemia-induced suppression of OPC differentiation via the phosphoinositide 3-kinase-Akt pathway. For the in vivo experiments, we used a mouse model of SIVD generated by bilateral common carotid artery stenosis. On day 28 after surgery, fingolimod ameliorated ischemia-induced demyelination and promoted oligodendrogenesis under prolonged cerebral hypoperfusion. The present study demonstrates that fingolimod can promote oligodendrogenesis under ischemic conditions and may be a therapeutic candidate for SIVD.