Abstract
Fingolimod (FTY720) was the first per os administered disease-modifying agent approved for the treatment of relapsing–remitting multiple sclerosis. It is thought that fingolimod modulates the immune response by activating sphingosine-1 phosphate receptor type 1 (S1P1) on lymphocytes following its in vivo phosphorylation. In addition to its immune-related effects, there is evidence that fingolimod exerts several other effects in the central nervous system, including regulation of the proliferation, survival and differentiation of various cell types and their precursors. In the present study, we have investigated the effect of fingolimod on the production of new neurons in the adult mouse hippocampus and the association of this effect with the ability for pattern separation, an established adult neurogenesis-dependent memory function. Immunofluorescence analysis after chronic administration of a physiologic dose of fingolimod (0.3 mg kg−1) revealed a significant increase in both the proliferation and the survival of neural progenitors in the area of dentate gyrus of hippocampus, compared with control animals. These effects were replicated in vitro, in cultures of murine hippocampal neural stem/precursor cells that express S1P1 receptor, suggesting cell-autonomous actions. The effects of fingolimod on neurogenesis were correlated to enhanced ability for context discrimination after fear conditioning. Since impairment of adult hippocampal neurogenesis and memory is a common feature of many neuropsychiatric conditions, fingolimod treatment may be beneficial in therapeutic armamentarium of these disorders.
Highlights
Recent research evidence indicates that neurogenesis is an important player in the plasticity of adult mammalian brain, responsible for several physiological functions including learning and memory.[1,2] The production rate of new neurons during adulthood, from endogenous neural stem cells (NSCs), takes place primarily in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) and in the subventricular zone.[3]
Fingolimod-induced adult neurogenesis in young but not in aged mice To test the effect of the chronic exposure to fingolimod on the proliferation of the NSCs in the adult and the aged DG, mice of three different age groups (3, 7 and 12 months) were administered i.p. 0.3 mg kg − 1 per day of fingolimod or the vehicle for 14 days, while they were administered 100 mg kg − 1 of the thymidine analog BrdU during the last 5 days of treatment—to mark all proliferative cells at the S phase of cell cycle—and killed 24 h later (Figure 1a)
Two-way analysis of variance (ANOVA) analysis for fingolimod treatment and age revealed that the number of proliferating, BrdU+, neural stem/precursor cells (NS/PCs) in the SGZ was significantly decreased with age
Summary
Recent research evidence indicates that neurogenesis is an important player in the plasticity of adult mammalian brain, responsible for several physiological functions including learning and memory.[1,2] The production rate of new neurons during adulthood, from endogenous neural stem cells (NSCs), takes place primarily in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) and in the subventricular zone.[3]. MS is a chronic autoimmune demyelinating disorder, which leads to neurodegeneration and brain atrophy in various regions including the hippocampus[7] and is accompanied by physical disability and cognitive decline, with memory loss being one of its major manifestations. Fingolimod exerts its beneficial effects on relapsing–remitting MS by sequestering lymphocytes within the lymph node.[8] there is increasing evidence suggesting that fingolimod affects the function of various cell types in the CNS including astrocytes, oligodendrocytes, neurons and their progenitors.[9,10,11]
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