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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

Antidepressant-like activity of fingolimod in mice chronically treated with corticosterone The design of the experiment is shown in (A). Mice were treated systemically with corticosterone (20 mg kg−1, s.c.) or vehicle (Ctrl) for 3 weeks, tested for depressive-like behavior in the forced swim test (FST) and sucrose preference test (SPT), and then treated i.p. once daily for 4 weeks with either saline (both groups) or fingolimod (3 mg kg−1, only the corticosterone group). All data of the FST in Ctrl mice and in mice treated with corticosterone (n = 11 and 22, respectively) are shown in B, where data (means + SEM) are expressed as the difference of immobility time (Δ) between values obtained at week 3 and time 0. *P < 0.05 (Student’s t-test; t(31) = 2.14) versus unstressed mice. Mice responders (n = 17) and nonresponders (n = 6) to corticosterone are shown in (C), where the cutoff value for resilience was considered <0.20 Standard Deviation Score (SDS) with respect to the mean value of immobility time in control mice treated with vehicle. The effect of fingolimod on the immobility time in the FST is shown in (D), where data (means + SEM) are expressed as the difference of immobility time (Δ) between values obtained at week 7 and week 3. *P < 0.05 (Student’s t-test; t(15) = 2.33) versus mice treated with saline (n = 7 in both groups). Absolute values of immobility time (means + SEM) in mice treated with saline or fingolimod are shown in (E). *P = 0.05 (Student’s t test; t15 = 2.09) versus saline.
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fig07: Antidepressant-like activity of fingolimod in mice chronically treated with corticosterone The design of the experiment is shown in (A). Mice were treated systemically with corticosterone (20 mg kg−1, s.c.) or vehicle (Ctrl) for 3 weeks, tested for depressive-like behavior in the forced swim test (FST) and sucrose preference test (SPT), and then treated i.p. once daily for 4 weeks with either saline (both groups) or fingolimod (3 mg kg−1, only the corticosterone group). All data of the FST in Ctrl mice and in mice treated with corticosterone (n = 11 and 22, respectively) are shown in B, where data (means + SEM) are expressed as the difference of immobility time (Δ) between values obtained at week 3 and time 0. *P < 0.05 (Student’s t-test; t(31) = 2.14) versus unstressed mice. Mice responders (n = 17) and nonresponders (n = 6) to corticosterone are shown in (C), where the cutoff value for resilience was considered <0.20 Standard Deviation Score (SDS) with respect to the mean value of immobility time in control mice treated with vehicle. The effect of fingolimod on the immobility time in the FST is shown in (D), where data (means + SEM) are expressed as the difference of immobility time (Δ) between values obtained at week 7 and week 3. *P < 0.05 (Student’s t-test; t(15) = 2.33) versus mice treated with saline (n = 7 in both groups). Absolute values of immobility time (means + SEM) in mice treated with saline or fingolimod are shown in (E). *P = 0.05 (Student’s t test; t15 = 2.09) versus 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)

Antidepressant-like activity of fingolimod in mice chronically treated with corticosterone The design of the experiment is shown in (A). Mice were treated systemically with corticosterone (20 mg kg−1, s.c.) or vehicle (Ctrl) for 3 weeks, tested for depressive-like behavior in the forced swim test (FST) and sucrose preference test (SPT), and then treated i.p. once daily for 4 weeks with either saline (both groups) or fingolimod (3 mg kg−1, only the corticosterone group). All data of the FST in Ctrl mice and in mice treated with corticosterone (n = 11 and 22, respectively) are shown in B, where data (means + SEM) are expressed as the difference of immobility time (Δ) between values obtained at week 3 and time 0. *P < 0.05 (Student’s t-test; t(31) = 2.14) versus unstressed mice. Mice responders (n = 17) and nonresponders (n = 6) to corticosterone are shown in (C), where the cutoff value for resilience was considered <0.20 Standard Deviation Score (SDS) with respect to the mean value of immobility time in control mice treated with vehicle. The effect of fingolimod on the immobility time in the FST is shown in (D), where data (means + SEM) are expressed as the difference of immobility time (Δ) between values obtained at week 7 and week 3. *P < 0.05 (Student’s t-test; t(15) = 2.33) versus mice treated with saline (n = 7 in both groups). Absolute values of immobility time (means + SEM) in mice treated with saline or fingolimod are shown in (E). *P = 0.05 (Student’s t test; t15 = 2.09) versus saline.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig07: Antidepressant-like activity of fingolimod in mice chronically treated with corticosterone The design of the experiment is shown in (A). Mice were treated systemically with corticosterone (20 mg kg−1, s.c.) or vehicle (Ctrl) for 3 weeks, tested for depressive-like behavior in the forced swim test (FST) and sucrose preference test (SPT), and then treated i.p. once daily for 4 weeks with either saline (both groups) or fingolimod (3 mg kg−1, only the corticosterone group). All data of the FST in Ctrl mice and in mice treated with corticosterone (n = 11 and 22, respectively) are shown in B, where data (means + SEM) are expressed as the difference of immobility time (Δ) between values obtained at week 3 and time 0. *P < 0.05 (Student’s t-test; t(31) = 2.14) versus unstressed mice. Mice responders (n = 17) and nonresponders (n = 6) to corticosterone are shown in (C), where the cutoff value for resilience was considered <0.20 Standard Deviation Score (SDS) with respect to the mean value of immobility time in control mice treated with vehicle. The effect of fingolimod on the immobility time in the FST is shown in (D), where data (means + SEM) are expressed as the difference of immobility time (Δ) between values obtained at week 7 and week 3. *P < 0.05 (Student’s t-test; t(15) = 2.33) versus mice treated with saline (n = 7 in both groups). Absolute values of immobility time (means + SEM) in mice treated with saline or fingolimod are shown in (E). *P = 0.05 (Student’s t test; t15 = 2.09) versus 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