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Neurogenic effects of fingolimod in hippocampus, affecting fear memory.

Paschalis Efstathopoulos1, 2*, Alexandra Kourgiantaki1, 2, Kyriaki Sidiropoulou3, Despoina Kortesidou3, Ioannis Charalampopoulos1, 2 and Achilleas Gravanis1, 2
  • 1 Foundation Research and Technology Hellas (FORTH), Greece
  • 2 Medical School, University of Crete, Pharmacology, Greece
  • 3 University of Crete, Biology, Greece

Fingolimod (FTY720; Gilenya™,Novartis Pharma AG) is a recently developed Sphingosine-1-Phosphate (S1P) analogue, orally administered as a new therapeutic agent in Multiple Sclerosis (MS) (Brinkmann V. et al. 2010). S1P receptors (S1PRs) are expressed in various sites in the CNS including the subventricular zone (Waeber C. et al. 1999; Choi J.W. et al. 2013) while endogenous S1P was shown to induce proliferation and morphological changes in embryonic hippocampal neural progenitors in culture (Harada J. et al. 2004). In this study we investigated the effects of fingolimod on adult rodent hippocampal neurogenesis and their possible functional role. To this aim, thymidine analogue BrdU was injected at the end or before a 2-week i.p. administration of a therapeutic dose of Fingolimod (0,3 mg/kg) in young and old mice. Stereological counts of BrdU+ cells revealed significant increase in both proliferation, and survival of neural stem cells (NSC) in the area of Dentate Gyrus (DG) of the hippocampus, compared to control untreated animals of young but not old ages. In the case of survival assessment, most of the BrdU + cells were also positive for NeuN, suggesting an increase of newly formed neurons. The increase in proliferation rate of NSC was also confirmed by BrdU uptake in hippocampal NSC cultures in vitro, implying that the effects of fingolimod are cell autonomous. Immunohistochemical analysis showed that S1PR was not co-localized with GFAP+ cells in the Subgranular zone (SGZ) of the DG, but was strongly co-localized with transcription factor MASH1 and weakly with DcX or PSA-NCAM positive neural progenitors. These findings suggest that expression of S1PR1 in the SGZ is restricted to transit amplifying neural progenitors and maintained also in the stage of neuroblast. In addition, the effects of Fingolimod in DG neurogenesis were positively correlated to enhanced fear memory and increased context discrimination, an established DG-dependent cognitive task (Saxa D. et al. 2006; Sahay A. et al. 2011). Conclusively, our data suggest that Fingolimod increases neurogenesis in adult hippocampus and improves memory function.

Acknowledgements

Milopotamitaki Klairi, karali kanelina

References

Brinkmann, V., Billich, A., Baumruker, T., Heining, P., Schmouder, R., Francis, G., Aradhye, S., and Burtin, P. (2010). Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nature Reviews Drug Discovery 9, 883-897.

Waeber C and Chiu ML (1999) In vitro autoradiographic visualization of guanosine-5'-O-(3-[35S]thio)triphosphate binding stimulated by sphingosine 1-phosphate and lysophosphatidic acid. Journal of Neurochemistry 73:1212-1221.

Choi, J.W., and Chun, J. (2013). Lysophospholipids and their receptors in the central nervous system. Biochimica Biophysica Acta 1831, 20-32.

Harada, J., Foley, M., Moskowitz, M.A., and Waeber, C. (2004). Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. Journal of Neurochemistry 88, 1026-1039.

Sahay, A., Scobie, K.N., Hill, A.S., O'Carroll, C.M., Kheirbek, M.A., Burghardt, N.S., Fenton, A.A., Dranovsky, A., and Hen, R. (2011). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466-470.

Saxe MD, Battaglia F, Wang JW, Malleret G, David DJ, Monckton JE, Garcia AD, Sofroniew MV, Kandel ER, Santarelli L, Hen R and Drew MR (2006) Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. PNAS 103:17501-17506.

Keywords: Neurogenesis, fingolimod, Fear conditioning, Memory, Neural Stem Cells

Conference: 4th NAMASEN Training Workshop - Dendrites 2014, Heraklion, Greece, 1 Jul - 4 Jul, 2014.

Presentation Type: Poster presentation

Topic: molecular pathways and signaling networks

Citation: Efstathopoulos P, Kourgiantaki A, Sidiropoulou K, Kortesidou D, Charalampopoulos I and Gravanis A (2014). Neurogenic effects of fingolimod in hippocampus, affecting fear memory.. Front. Syst. Neurosci. Conference Abstract: 4th NAMASEN Training Workshop - Dendrites 2014. doi: 10.3389/conf.fnsys.2014.05.00002

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Received: 29 May 2014; Published Online: 12 Jun 2014.

* Correspondence: Mr. Paschalis Efstathopoulos, Foundation Research and Technology Hellas (FORTH), Heraklion, Greece, pefstatho@gmail.com