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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 had no effect on anxiety-like behavior in the EPM or spatial learning in the 1 day Morris water maze. The design of experiment #2 is show in (A). Single values at the EPM are shown in (B). Values (means + SEM) of the three blocks of trials in the water maze are shown in (C). n = 8 and 11 for unstressed mice treated with saline and fingolimod, respectively; n = 8 and 12 for stressed mice treated with saline and fingolimod, respectively. Two-way ANOVA for repeated measures showed a significant difference among the blocks (F2,36 = 7.54; P < 0.05), a significant effect of CUS (F1,36 = 13.44; P < 0.05), and no effect of treatment (F1,36 = 0.048; P > 0.05) or CUS × treatment (F1,36 = 2.14; P > 0.05). Single values of the probe test (the time spent in the quarter of the maze previously associated with the platform) are shown in (D). EPM, elevated plus maze; MWM, morris water maze; SI, social interaction test.
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fig04: Fingolimod treatment had no effect on anxiety-like behavior in the EPM or spatial learning in the 1 day Morris water maze. The design of experiment #2 is show in (A). Single values at the EPM are shown in (B). Values (means + SEM) of the three blocks of trials in the water maze are shown in (C). n = 8 and 11 for unstressed mice treated with saline and fingolimod, respectively; n = 8 and 12 for stressed mice treated with saline and fingolimod, respectively. Two-way ANOVA for repeated measures showed a significant difference among the blocks (F2,36 = 7.54; P < 0.05), a significant effect of CUS (F1,36 = 13.44; P < 0.05), and no effect of treatment (F1,36 = 0.048; P > 0.05) or CUS × treatment (F1,36 = 2.14; P > 0.05). Single values of the probe test (the time spent in the quarter of the maze previously associated with the platform) are shown in (D). EPM, elevated plus maze; MWM, morris water maze; SI, social interaction test.

Mentions: The second set of mice (Fig.4A) was used for a battery of behavioral tests including the elevated plus maze (EPM, performed prior to the onset of CUS and 12 h after the last administration of saline or fingolimod), the “single-day” Morris water maze (MWM) (performed 3 days after the end of treatments), and the social interaction test (performed 4 days after the MWM). At the end of the last behavioral session, all mice were treated with 5-bromo-2′-deoxyuridine (BrdU; Sigma Aldrich) and killed after 2 days for the assessment of hippocampal neurogenesis.


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 had no effect on anxiety-like behavior in the EPM or spatial learning in the 1 day Morris water maze. The design of experiment #2 is show in (A). Single values at the EPM are shown in (B). Values (means + SEM) of the three blocks of trials in the water maze are shown in (C). n = 8 and 11 for unstressed mice treated with saline and fingolimod, respectively; n = 8 and 12 for stressed mice treated with saline and fingolimod, respectively. Two-way ANOVA for repeated measures showed a significant difference among the blocks (F2,36 = 7.54; P < 0.05), a significant effect of CUS (F1,36 = 13.44; P < 0.05), and no effect of treatment (F1,36 = 0.048; P > 0.05) or CUS × treatment (F1,36 = 2.14; P > 0.05). Single values of the probe test (the time spent in the quarter of the maze previously associated with the platform) are shown in (D). EPM, elevated plus maze; MWM, morris water maze; SI, social interaction test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig04: Fingolimod treatment had no effect on anxiety-like behavior in the EPM or spatial learning in the 1 day Morris water maze. The design of experiment #2 is show in (A). Single values at the EPM are shown in (B). Values (means + SEM) of the three blocks of trials in the water maze are shown in (C). n = 8 and 11 for unstressed mice treated with saline and fingolimod, respectively; n = 8 and 12 for stressed mice treated with saline and fingolimod, respectively. Two-way ANOVA for repeated measures showed a significant difference among the blocks (F2,36 = 7.54; P < 0.05), a significant effect of CUS (F1,36 = 13.44; P < 0.05), and no effect of treatment (F1,36 = 0.048; P > 0.05) or CUS × treatment (F1,36 = 2.14; P > 0.05). Single values of the probe test (the time spent in the quarter of the maze previously associated with the platform) are shown in (D). EPM, elevated plus maze; MWM, morris water maze; SI, social interaction test.
Mentions: The second set of mice (Fig.4A) was used for a battery of behavioral tests including the elevated plus maze (EPM, performed prior to the onset of CUS and 12 h after the last administration of saline or fingolimod), the “single-day” Morris water maze (MWM) (performed 3 days after the end of treatments), and the social interaction test (performed 4 days after the MWM). At the end of the last behavioral session, all mice were treated with 5-bromo-2′-deoxyuridine (BrdU; Sigma Aldrich) and killed after 2 days for the assessment of hippocampal neurogenesis.

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