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Antidepressant activity of fingolimod in mice.
di Nuzzo, Luigi; Orlando, Rosamaria; Tognoli, Cristina; Di Pietro, Paola; Bertini, Giuseppe; Miele, Jessica; Bucci, Domenico; Motolese, Marta; Scaccianoce, Sergio; Caruso, Alessandra; Mauro, Gianluca; De Lucia, Carmine; Battaglia, Giuseppe; Bruno, Valeria; Fabene, Paolo Francesco; Nicoletti, Ferdinando.
Afiliação
  • di Nuzzo L; Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
  • Orlando R; IRCCS Associazione Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging Troina, Italy.
  • Tognoli C; Department of Neurological and Movement Sciences, University of Verona Verona, Italy.
  • Di Pietro P; IRCCS Neuromed Pozzilli, Italy.
  • Bertini G; Department of Neurological and Movement Sciences, University of Verona Verona, Italy.
  • Miele J; Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
  • Bucci D; IRCCS Neuromed Pozzilli, Italy.
  • Motolese M; IRCCS Neuromed Pozzilli, Italy.
  • Scaccianoce S; Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
  • Caruso A; Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
  • Mauro G; Institute of Psychiatry, Catholic University of Sacred Heart Rome, Italy.
  • De Lucia C; Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.
  • Battaglia G; IRCCS Neuromed Pozzilli, Italy.
  • Bruno V; Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy ; IRCCS Neuromed Pozzilli, Italy.
  • Fabene PF; Department of Neurological and Movement Sciences, University of Verona Verona, Italy.
  • Nicoletti F; Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy ; IRCCS Neuromed Pozzilli, Italy.
Pharmacol Res Perspect ; 3(3): e00135, 2015 Jun.
Article em En | MEDLINE | ID: mdl-26171219
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.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2015 Tipo de documento: Article