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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 exposed to chronic unpredictable stress (CUS). The design of experiment #1 is shown in (A). Mice were exposed to CUS for 4 weeks, with 1 day of interval after the end of the third week for the analysis depressive-like behavior in the forced swim test (FST) and sucrose preference test (SPT). A four-week treatment with saline or Fingolimod (3 mg kg−1, once daily) was started at the beginning of the 4th week of CUS. Mice were killed 1 day after the last FST. Cumulative data of the FST in all unstressed and CUS (stressed) mice (n = 21 and 38, respectively) is 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(57) = 3.53) versus unstressed mice. Mice resilient (n = 13) and nonresilient (n = 25) to stress are shown in (C), where the cutoff value for resilience was considered <1 Standard Deviation Score (SDS) with respect to the mean value of immobility time in unstressed mice. SDS = (x − μ)/σ, where x = the immobility time of each CUS mouse; μ and σ = mean and SD of the immobility time in unstressed mice. The overall 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(20) = 2.62) versus mice treated with saline (n = 9 and 13 mice treated with saline and Fingolimod, respectively). Mice responsive and not responsive to the antidepressant-like activity of Fingolimod are shown in (E), where the cutoff for drug response was considered ≤1 SDS with respect to the mean value of immobility time in CUS mice treated with saline. Absolute values of immobility time in nonresilient CUS mice treated with saline (n = 9) or Fingolimod (n = 13, divided into nine responders and four nonresponders) are shown in (F), where values are means + SEM. One-way ANOVA + Tukey’s t-test; F(2,19) = 12.86; P < 0.05; post hoc analysis: (*) P < 0.05 versus all other values. In (G), data obtained in responders and nonresponders to Fingolimod were combined and compared to data obtained in mice treated with saline. *P < 0.05 (Student’s t-test; t19 = 2.141).
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fig01: Antidepressant-like activity of Fingolimod in mice exposed to chronic unpredictable stress (CUS). The design of experiment #1 is shown in (A). Mice were exposed to CUS for 4 weeks, with 1 day of interval after the end of the third week for the analysis depressive-like behavior in the forced swim test (FST) and sucrose preference test (SPT). A four-week treatment with saline or Fingolimod (3 mg kg−1, once daily) was started at the beginning of the 4th week of CUS. Mice were killed 1 day after the last FST. Cumulative data of the FST in all unstressed and CUS (stressed) mice (n = 21 and 38, respectively) is 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(57) = 3.53) versus unstressed mice. Mice resilient (n = 13) and nonresilient (n = 25) to stress are shown in (C), where the cutoff value for resilience was considered <1 Standard Deviation Score (SDS) with respect to the mean value of immobility time in unstressed mice. SDS = (x − μ)/σ, where x = the immobility time of each CUS mouse; μ and σ = mean and SD of the immobility time in unstressed mice. The overall 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(20) = 2.62) versus mice treated with saline (n = 9 and 13 mice treated with saline and Fingolimod, respectively). Mice responsive and not responsive to the antidepressant-like activity of Fingolimod are shown in (E), where the cutoff for drug response was considered ≤1 SDS with respect to the mean value of immobility time in CUS mice treated with saline. Absolute values of immobility time in nonresilient CUS mice treated with saline (n = 9) or Fingolimod (n = 13, divided into nine responders and four nonresponders) are shown in (F), where values are means + SEM. One-way ANOVA + Tukey’s t-test; F(2,19) = 12.86; P < 0.05; post hoc analysis: (*) P < 0.05 versus all other values. In (G), data obtained in responders and nonresponders to Fingolimod were combined and compared to data obtained in mice treated with saline. *P < 0.05 (Student’s t-test; t19 = 2.141).

Mentions: We have tested the antidepressant-like activity of fingolimod using two established models of depression in mice: (i) exposure to CUS; and (ii) chronic administration of corticosterone. In the CUS paradigm, we used two sets of mice, each including the following groups: (i) unstressed mice treated i.p. with saline or fingolimod (3 mg kg−1) for 4 weeks; and (ii) mice exposed to CUS daily for 4 weeks and chronically treated with saline or fingolimod (see above) starting after 3 weeks of CUS. The first set of mice (Fig.1A) was used for the assessment of depressive-like behavior in the forced swim test (FST) prior to the onset of CUS, at the end of the third week of CUS, and then 30 min after the last administration of saline or fingolimod. The sucrose preference test (SPT) was performed at baseline and after 3 weeks of CUS, 1 h after the FST. Mice were killed 24 h after the last FST session for biochemical analysis.


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 exposed to chronic unpredictable stress (CUS). The design of experiment #1 is shown in (A). Mice were exposed to CUS for 4 weeks, with 1 day of interval after the end of the third week for the analysis depressive-like behavior in the forced swim test (FST) and sucrose preference test (SPT). A four-week treatment with saline or Fingolimod (3 mg kg−1, once daily) was started at the beginning of the 4th week of CUS. Mice were killed 1 day after the last FST. Cumulative data of the FST in all unstressed and CUS (stressed) mice (n = 21 and 38, respectively) is 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(57) = 3.53) versus unstressed mice. Mice resilient (n = 13) and nonresilient (n = 25) to stress are shown in (C), where the cutoff value for resilience was considered <1 Standard Deviation Score (SDS) with respect to the mean value of immobility time in unstressed mice. SDS = (x − μ)/σ, where x = the immobility time of each CUS mouse; μ and σ = mean and SD of the immobility time in unstressed mice. The overall 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(20) = 2.62) versus mice treated with saline (n = 9 and 13 mice treated with saline and Fingolimod, respectively). Mice responsive and not responsive to the antidepressant-like activity of Fingolimod are shown in (E), where the cutoff for drug response was considered ≤1 SDS with respect to the mean value of immobility time in CUS mice treated with saline. Absolute values of immobility time in nonresilient CUS mice treated with saline (n = 9) or Fingolimod (n = 13, divided into nine responders and four nonresponders) are shown in (F), where values are means + SEM. One-way ANOVA + Tukey’s t-test; F(2,19) = 12.86; P < 0.05; post hoc analysis: (*) P < 0.05 versus all other values. In (G), data obtained in responders and nonresponders to Fingolimod were combined and compared to data obtained in mice treated with saline. *P < 0.05 (Student’s t-test; t19 = 2.141).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig01: Antidepressant-like activity of Fingolimod in mice exposed to chronic unpredictable stress (CUS). The design of experiment #1 is shown in (A). Mice were exposed to CUS for 4 weeks, with 1 day of interval after the end of the third week for the analysis depressive-like behavior in the forced swim test (FST) and sucrose preference test (SPT). A four-week treatment with saline or Fingolimod (3 mg kg−1, once daily) was started at the beginning of the 4th week of CUS. Mice were killed 1 day after the last FST. Cumulative data of the FST in all unstressed and CUS (stressed) mice (n = 21 and 38, respectively) is 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(57) = 3.53) versus unstressed mice. Mice resilient (n = 13) and nonresilient (n = 25) to stress are shown in (C), where the cutoff value for resilience was considered <1 Standard Deviation Score (SDS) with respect to the mean value of immobility time in unstressed mice. SDS = (x − μ)/σ, where x = the immobility time of each CUS mouse; μ and σ = mean and SD of the immobility time in unstressed mice. The overall 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(20) = 2.62) versus mice treated with saline (n = 9 and 13 mice treated with saline and Fingolimod, respectively). Mice responsive and not responsive to the antidepressant-like activity of Fingolimod are shown in (E), where the cutoff for drug response was considered ≤1 SDS with respect to the mean value of immobility time in CUS mice treated with saline. Absolute values of immobility time in nonresilient CUS mice treated with saline (n = 9) or Fingolimod (n = 13, divided into nine responders and four nonresponders) are shown in (F), where values are means + SEM. One-way ANOVA + Tukey’s t-test; F(2,19) = 12.86; P < 0.05; post hoc analysis: (*) P < 0.05 versus all other values. In (G), data obtained in responders and nonresponders to Fingolimod were combined and compared to data obtained in mice treated with saline. *P < 0.05 (Student’s t-test; t19 = 2.141).
Mentions: We have tested the antidepressant-like activity of fingolimod using two established models of depression in mice: (i) exposure to CUS; and (ii) chronic administration of corticosterone. In the CUS paradigm, we used two sets of mice, each including the following groups: (i) unstressed mice treated i.p. with saline or fingolimod (3 mg kg−1) for 4 weeks; and (ii) mice exposed to CUS daily for 4 weeks and chronically treated with saline or fingolimod (see above) starting after 3 weeks of CUS. The first set of mice (Fig.1A) was used for the assessment of depressive-like behavior in the forced swim test (FST) prior to the onset of CUS, at the end of the third week of CUS, and then 30 min after the last administration of saline or fingolimod. The sucrose preference test (SPT) was performed at baseline and after 3 weeks of CUS, 1 h after the FST. Mice were killed 24 h after the last FST session for biochemical analysis.

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