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di Nuzzo L, Orlando R, Tognoli C, et al. Antidepressant activity of fingolimod in mice. Pharmacol Res Perspect. 2015;3(3):e00135doi: 10.1002/prp2.135.
di Nuzzo, L., Orlando, R., Tognoli, C., Di Pietro, P., Bertini, G., Miele, J., Bucci, D., Motolese, M., Scaccianoce, S., Caruso, A., Mauro, G., De Lucia, C., Battaglia, G., Bruno, V., Fabene, P. F., & Nicoletti, F. (2015). Antidepressant activity of fingolimod in mice. Pharmacology research & perspectives, 3(3), e00135. https://doi.org/10.1002/prp2.135
di Nuzzo, Luigi, et al. "Antidepressant activity of fingolimod in mice." Pharmacology research & perspectives vol. 3,3 (2015): e00135. doi: https://doi.org/10.1002/prp2.135
di Nuzzo L, Orlando R, Tognoli C, Di Pietro P, Bertini G, Miele J, Bucci D, Motolese M, Scaccianoce S, Caruso A, Mauro G, De Lucia C, Battaglia G, Bruno V, Fabene PF, Nicoletti F. Antidepressant activity of fingolimod in mice. Pharmacol Res Perspect. 2015 Jun;3(3):e00135. doi: 10.1002/prp2.135. Epub 2015 May 24. PMID: 26171219; PMCID: PMC4492751.
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Pharmacol Res Perspect. 2015 Jun;3(3):e00135. doi: 10.1002/prp2.135. Epub 2015 May 24.

Antidepressant activity of fingolimod in mice.

Pharmacology research & perspectives

Luigi di Nuzzo, Rosamaria Orlando, Cristina Tognoli, Paola Di Pietro, Giuseppe Bertini, Jessica Miele, Domenico Bucci, Marta Motolese, Sergio Scaccianoce, Alessandra Caruso, Gianluca Mauro, Carmine De Lucia, Giuseppe Battaglia, Valeria Bruno, Paolo Francesco Fabene, Ferdinando Nicoletti

Affiliations

  1. Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
  2. IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging Troina, Italy.
  3. Department of Neurological and Movement Sciences, University of Verona Verona, Italy.
  4. IRCCS Neuromed Pozzilli, Italy.
  5. Institute of Psychiatry, Catholic University of Sacred Heart Rome, Italy.
  6. Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy ; IRCCS Neuromed Pozzilli, Italy.

PMID: 26171219 PMCID: PMC4492751 DOI: 10.1002/prp2.135

Abstract

Recent findings indicate that fingolimod, the first oral drug approved for the treatment of multiple sclerosis (MS), acts as a direct inhibitor of histone deacetylases (HDACs) and enhances the production of brain-derived neurotrophic factor (BDNF) in the CNS. Both mechanisms are relevant to the pathophysiology and treatment of major depression. We examined the antidepressant activity of fingolimod in mice subjected to chronic unpredictable stress (CUS), a model of reactive depression endowed with face and pharmacological validity. Chronic treatment with fingolimod (3 mg kg(-1), i.p., once a day for 4 weeks) reduced the immobility time in the forced swim test (FST) in a large proportion of CUS mice. This treatment also caused anxiogenic-like effects in the social interaction test without affecting anxiety-like behavior in the elevated plus maze or spatial learning in the water maze. CUS mice showed reduced BDNF levels and enhanced HDAC2 levels in the hippocampus. These changes were reversed by fingolimod exclusively in mice that showed a behavioral response to the drug in the FST. Fingolimod treatment also enhanced H3 histone K14-acetylation and adult neurogenesis in the hippocampus of CUS mice. Fingolimod did not affect most of the parameters we have tested in unstressed control mice. The antidepressant-like activity of fingolimod was confirmed in mice chronically treated with corticosterone. These findings show for the first time that fingolimod exerts antidepressant-like effect acting in a "disease-dependent" manner, and raise the interesting possibility that the drug could relieve depressive symptoms in MS patients independently of its disease-modifying effect on MS.

Keywords: BDNF; chronic stress; depression; fingolimod; hippocampus

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