Fingolimod induces neurogenesis in adult mouse hippocampus and improves contextual fear memory.
Fingolimod induces neurogenesis in adult mouse hippocampus and improves contextual fear memory.
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DOI：
10.1038/tp.2015.179
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发表时间：
2015-11-24
影响因子：
6.8
通讯作者：
Charalampopoulos I
中科院分区：
文献类型：
--
作者：
Efstathopoulos P;Kourgiantaki A;Karali K;Sidiropoulou K;Margioris AN;Gravanis A;Charalampopoulos I
Fingolimod(FTY720)是第一个经口服被批准用于治疗复发缓解型多发性硬化症的疾病改良剂。目前认为，Fingolimod在体内通过激活淋巴细胞上的鞘氨醇-1磷酸受体1(S1P1)来调节免疫反应。除了与免疫相关的作用外，有证据表明，Fingolimod还在中枢神经系统中发挥其他几种作用，包括调节各种类型细胞及其前体的增殖、存活和分化。在本研究中，我们研究了Fingolimod对成年小鼠海马区新神经元产生的影响，以及这种影响与模式分离能力的关系，模式分离是一种已建立的成人神经发生依赖的记忆功能。长期给予生理剂量的Fingolimod(0.3 mg kg−1)后，免疫荧光分析显示，与对照组相比，海马齿状回神经前体细胞的增殖和存活均显著增加。这些效应在体外培养的表达S1P1受体的小鼠海马神经干细胞/前体细胞中复制，表明了细胞自主作用。Fingolimod对神经发生的影响与恐惧条件反射后背景辨别能力的增强有关。由于成年海马神经发生和记忆障碍是许多神经精神疾病的共同特征，Fingolimod治疗可能对这些疾病的治疗有利。
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.
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DOI：
10.1093/brain/awn157
发表时间：
2008-09
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Chang A;Smith MC;Yin X;Fox RJ;Staugaitis SM;Trapp BD
通讯作者：
Trapp BD
DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
2.7
作者：
Fukumoto, Kazuya;Mizoguchi, Hiroyuki;Suzumura, Akio
通讯作者：
Suzumura, Akio
影响因子：
3.1
作者：
Asle-Rousta, Masoumeh;Kolahdooz, Zeynab;Dargahi, Leila
通讯作者：
Dargahi, Leila
影响因子：
4.7
作者：
Lee, J;Duan, W;Mattson, MP
通讯作者：
Mattson, MP