title: Antidepressant activity of fingolimod in mice.
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.
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: di Nuzzo
authors.affiliation: IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging Troina, Italy.
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Orlando
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona Verona, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tognoli
authors.affiliation: IRCCS Neuromed Pozzilli, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Pietro
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona Verona, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bertini
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Miele
authors.affiliation: IRCCS Neuromed Pozzilli, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Bucci
authors.affiliation: IRCCS Neuromed Pozzilli, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Motolese
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Scaccianoce
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Caruso
authors.affiliation: Institute of Psychiatry, Catholic University of Sacred Heart Rome, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Mauro
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: De Lucia
authors.affiliation: IRCCS Neuromed Pozzilli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy ; IRCCS Neuromed Pozzilli, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.affiliation: Department of Neurological and Movement Sciences, University of Verona Verona, Italy.
authors.forename: Paolo Francesco
authors.initials: PF
authors.lastname: Fabene
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy ; IRCCS Neuromed Pozzilli, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
keywords: BDNF; chronic stress; depression; fingolimod; hippocampus