Antidepressant activity of fingolimod in mice

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.

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

“…In fact, the antidepressant effects of fingolimod (3 mg/Kg, i.p. once a day for 4 weeks) have been reported in mice exposed to chronic unpredictable stress and in mice chronically treated with corticosterone, both of which represent models of depression [21] and in patients with relapsing-remitting multiple sclerosis, who switched from injectable disease-modifying therapy to fingolimod [73,74]. In our study, fingolimod did not affect anxiety-like behavior in the EPM test, similar to the findings by di Nuzzo et al [21] in mice.…”

“…As previously reported, this epigenetic regulation by fingolimod could also lead to an augmented expression of growth factors such as BDNF that play a fundamental role in synaptic plasticity process, which are involved in memory formation and retention [21,[80][81][82]. In any case, the role of HDAC modulation in epilepsy and more specifically in WAG/Rij rats still does not permit us to either support or discard its involvement in fingolimod effects, also considering the potential of HDAC modulation in epileptogenesis and animal behavior [34,83,84].…”

“…Two doses of fingolimod (1 and 3 mg/Kg/day; gift from Novartis Pharmaceutical Development, Basel, Switzerland) were used in this protocol section and were chosen according to previous studies [13,21,23,24]; the acute effects of fingolimod were always tested 1h after i.p. administration considering its known pharmacokinetic profile [44].…”

“…However, being a pro-drug, fingolimod (as well as sphingosine), is phosphorylated in vivo, by SphKs, into the active metabolite fingolimod phosphate (fingolimod-P or FTY720-P), which acts as a sphingosine 1-phosphate (S1P) receptor (S1PRs) modulator [12,13,15]. Furthermore, fingolimod has also receptorindependent effects, some of which are mediated by binding to intracellular targets of S1P [16], including the mammalian target of rapamycin (mTOR) signaling pathway [17][18][19] and histone deacetylases (HDACs) [20,21], whereas other effects could be linked to its ability to affect the metabolism and signaling of other lipids [16].…”

The Sphingosine 1-Phosphate Signaling Pathway in Epilepsy: A Possible Role for the Immunomodulator Drug Fingolimod in Epilepsy Treatment

“…Alzheimer's Disease Human cells and experimental models [1,106,111] Amyotrophic Lateral Sclerosis mSOD1 G93A mice [109] Anxiety Mouse model of chronic unpredictable stress [112] Brain Tumors Human cells and experimental models [1,113] Cerebral Malaria Human and experimental cerebral malaria [114] Depression Mouse model of chronic unpredictable stress [112] Epilepsy Lithium-pilocarpine model, PTZ model and WAG/Rij rat model [10,11,115] Huntington Disease R6/2 mouse model [107] Intracerebral Hemorrhage Several experimental models [1] Multiple Sclerosis Approved, in 2010, for the treatment of relapsing-remitting multiple sclerosis [1,50] Neuroblastoma Xenograft model [116] Parkinson's Disease A53T transgenic (Tg) mice [110] Rett Syndrome MeCP2 -deficient mice [117] Stroke Several experimental models and a clinical proof-of concept study [1,118]…”