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.