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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.

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New oral drugs have considerably enriched the therapeutic armamentarium for the treatment of multiple sclerosis. This review focuses on the molecular pharmacodynamics of fingolimod, dimethyl fumarate (BG-12), laquinimod, and teriflunomide. We specifically comment on the action of these drugs at three levels: 1) the regulation of the immune system; 2) the permeability of the blood–brain barrier; and 3) the central nervous system. Fingolimod phosphate (the active metabolite of fingolimod) has a unique mechanism of action and represents the first ligand of G-protein-coupled receptors (sphingosine-1-phosphate receptors) active in the treatment of multiple sclerosis. Dimethyl fumarate activates the nuclear factor (erythroid-derived 2)-related factor 2 pathway of cell defense as a result of an initial depletion of reduced glutathione. We discuss how this mechanism lies on the border between cell protection and toxicity. Laquinimod has multiple (but less defined) mechanisms of action, which make the drug slightly more effective on disability progression than on annualized relapse rate in clinical studies. Teriflunomide acts as a specific inhibitor of the de novo pyrimidine biosynthesis. We also discuss new unexpected mechanisms of these drugs, such as the induction of brain-derived neurotrophic factor by fingolimod and the possibility that laquinimod and teriflunomide regulate the kynurenine pathway of tryptophan metabolism.

IntroductionDecreased cognitive control over the urge to be involved in gambling activities is a core feature of gambling disorder (GD). Cognitive control can be conceptualized as the sum of high-order cognitive faculties interacting in the achievement of goal-oriented behaviors. As such, cognitive control can be differentiated into several cognitive sub-processes, such as response inhibition, conflict monitoring, decision-making and cognitive flexibility, all of which prove to be pivotal in GD clinical phenomenology.ObjectivesOver the past few years, several studies and reviews have indicated a lack of cognitive control in GD through self-report questionnaires and neurocognitive tasks. Conversely, there are only a limited number of neuroimaging studies, which investigate the neural mechanisms underlying diminished cognitive control in GD.AimsThis research aims to systematically review functional magnetic resonance imaging (fMRI) studies that target cognitive control in GD.MethodsA literature search was conducted in order to find appropriate published articles on fMRI studies in GD.ResultsFourteen fMRI studies were included. Depending on which neurocognitive task was employed, the studies were divided into five different sections: conflict monitoring, response inhibition, delay discounting, cognitive flexibility and decision-making.ConclusionsImpaired activity in prefrontal cortex may account for decreased cognitive control in GD, contributing to the progressive loss of control over gambling behaviors. However, the way in which cognitive control interacts with affective and motivational processes in GD is still matter of investigation. Among prefrontal areas, orbitofrontal cortex has been indicated as a possible nexus for sensory integration, value-based decision-making and emotional processing, thus contributing to both motivational and affective aspects of cognitive control.Disclosure of interestThe authors have not supplied their declaration of competing interest.