The sphingosine-1-phosphate analogue, FTY-720, promotes the proliferation of embryonic neural stem cells, enhances hippocampal neurogenesis and learning and memory abilities in adult mice.

Abstract

Fingolimod (FTY-720) is the first oral therapeutic drug approved for the relapsing-remitting forms of multiple sclerosis. Neural stem cells (NSCs) are capable of continuous self-renewal and differentiation. The dentate gyrus of the hippocampus in the adult mammalian brain contains a population of NSCs and is one of the regions where neurogenesis takes place. FTY-720 has been shown to have neuroprotective effects in several model systems, so we investigated the direct effects of FTY-720 on NSCs and adult neurogenesis. We assessed the effects of FTY-720 on the proliferation and differentiation of cultured embryonic hippocampal NSCs using the 5-bromo-2-deoxyuridine incorporation assay, the neurosphere formation assay and western blot analysis. Receptor selective agonists and antagonists were used to identify the mechanisms involved. Neurogenesis in the hippocampus of C57BL/6 mice was also assessed by immunohistochemistry. The Morris water maze and fear conditioning tests were used to detect the learning and memory abilities of mice. FTY-720 promoted the proliferation of embryonic hippocampal NSCs probably via the activation of ERK signalling, Gi/o proteins and S1P1 receptors. However, FTY-720 did not affect the differentiation of cultured hippocampal NSCs. In vivo, chronic treatment with FTY-720 promoted hippocampal neurogenesis in adult C57BL/6 mice and enhanced their learning and memory abilities. Our results suggest a new target for the activation of NSCs and provide an insight into the therapeutic effects of FTY-720 in neuropsychiatric disorders, neurodegenerative diseases and age-related cognitive decline where hippocampal neurogenesis is compromised.