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Antidepressant activity of fingolimod in mice.

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 - Pharmacol Res Perspect (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

Fingolimod treatment enhances adult neurogenesis in the hippocampal dentate gyrus of mice exposed to CUS. Stereological counts of BrdU+ or DCX+ cells in the dentate gyrus of unstressed and CUS (stressed) mice treated with saline or fingolimod are reported in (A) and (B), respectively. Representative images of BrdU or DCX staining are also shown. Values are means + SEM of 5 determinations per group in (A) and 4 determinations per group in (B). Two-way ANOVA + Fisher’ LSD; BrdU+ cells, stressed/unstressed: F(3,16) = 3.829, P > 0.05; drug treatment: F(3,16) = 4.366, P > 0.05; stressed/unstressed x drug treatment: F(3,16) = 5.273, P < 0.05; DCX+ cells, stressed/unstressed: F(3,12) = 2.483, P > 0.05; drug treatment: F(3,12) = 20.898, P < 0.05; stressed/unstressed × drug treatment: F(3,12) = 6.768, P < 0.05. Post hoc analysis: P < 0.05 versus the respective groups of unstressed mice treated with saline (*), or versus the respective groups of stressed mice treated with saline (#).
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fig06: Fingolimod treatment enhances adult neurogenesis in the hippocampal dentate gyrus of mice exposed to CUS. Stereological counts of BrdU+ or DCX+ cells in the dentate gyrus of unstressed and CUS (stressed) mice treated with saline or fingolimod are reported in (A) and (B), respectively. Representative images of BrdU or DCX staining are also shown. Values are means + SEM of 5 determinations per group in (A) and 4 determinations per group in (B). Two-way ANOVA + Fisher’ LSD; BrdU+ cells, stressed/unstressed: F(3,16) = 3.829, P > 0.05; drug treatment: F(3,16) = 4.366, P > 0.05; stressed/unstressed x drug treatment: F(3,16) = 5.273, P < 0.05; DCX+ cells, stressed/unstressed: F(3,12) = 2.483, P > 0.05; drug treatment: F(3,12) = 20.898, P < 0.05; stressed/unstressed × drug treatment: F(3,12) = 6.768, P < 0.05. Post hoc analysis: P < 0.05 versus the respective groups of unstressed mice treated with saline (*), or versus the respective groups of stressed mice treated with saline (#).

Mentions: Statistical analysis was performed by Student’s t-test (Figs.1B, D, G, and 7B, D, E), one-way anaylsis of variance (ANOVA) + Tukey’s t-test (Figs.1F, 2G, 3A, and B), or two-way ANOVA + Fisher’s LSD (Figs.2A, C, E, F, 4C, 5A, B, and 6A, B).


Antidepressant activity of fingolimod in mice.

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 - Pharmacol Res Perspect (2015)

Fingolimod treatment enhances adult neurogenesis in the hippocampal dentate gyrus of mice exposed to CUS. Stereological counts of BrdU+ or DCX+ cells in the dentate gyrus of unstressed and CUS (stressed) mice treated with saline or fingolimod are reported in (A) and (B), respectively. Representative images of BrdU or DCX staining are also shown. Values are means + SEM of 5 determinations per group in (A) and 4 determinations per group in (B). Two-way ANOVA + Fisher’ LSD; BrdU+ cells, stressed/unstressed: F(3,16) = 3.829, P > 0.05; drug treatment: F(3,16) = 4.366, P > 0.05; stressed/unstressed x drug treatment: F(3,16) = 5.273, P < 0.05; DCX+ cells, stressed/unstressed: F(3,12) = 2.483, P > 0.05; drug treatment: F(3,12) = 20.898, P < 0.05; stressed/unstressed × drug treatment: F(3,12) = 6.768, P < 0.05. Post hoc analysis: P < 0.05 versus the respective groups of unstressed mice treated with saline (*), or versus the respective groups of stressed mice treated with saline (#).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4492751&req=5

fig06: Fingolimod treatment enhances adult neurogenesis in the hippocampal dentate gyrus of mice exposed to CUS. Stereological counts of BrdU+ or DCX+ cells in the dentate gyrus of unstressed and CUS (stressed) mice treated with saline or fingolimod are reported in (A) and (B), respectively. Representative images of BrdU or DCX staining are also shown. Values are means + SEM of 5 determinations per group in (A) and 4 determinations per group in (B). Two-way ANOVA + Fisher’ LSD; BrdU+ cells, stressed/unstressed: F(3,16) = 3.829, P > 0.05; drug treatment: F(3,16) = 4.366, P > 0.05; stressed/unstressed x drug treatment: F(3,16) = 5.273, P < 0.05; DCX+ cells, stressed/unstressed: F(3,12) = 2.483, P > 0.05; drug treatment: F(3,12) = 20.898, P < 0.05; stressed/unstressed × drug treatment: F(3,12) = 6.768, P < 0.05. Post hoc analysis: P < 0.05 versus the respective groups of unstressed mice treated with saline (*), or versus the respective groups of stressed mice treated with saline (#).
Mentions: Statistical analysis was performed by Student’s t-test (Figs.1B, D, G, and 7B, D, E), one-way anaylsis of variance (ANOVA) + Tukey’s t-test (Figs.1F, 2G, 3A, and B), or two-way ANOVA + Fisher’s LSD (Figs.2A, C, E, F, 4C, 5A, B, and 6A, B).

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Pharmacology, University Sapienza of Rome Rome, Italy.

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.

No MeSH data available.


Related in: MedlinePlus