Abstract
Depression is a widespread chronic medical illness affecting thoughts, mood, and physical health. However, the limited and delayed therapeutic efficacy of monoaminergic drugs has led to intensive research efforts to develop novel antidepressants. ARN-3236 is the first potent and selective inhibitor of salt-inducible kinase 2 (SIK2). In this study, a multidisciplinary approach was used to explore the antidepressant-like actions of ARN-3236 in mice. Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, high performance liquid chromatography-tandem mass spectrometry, stereotactic infusion, viral-mediated gene transfer, western blotting, co-immunoprecipitation and immunofluorescence were used together. It was found that ARN-3236 could penetrate the blood-brain barrier. Repeated ARN-3236 administration induced significant antidepressant-like effects in both the CSDS and CUMS models of depression, accompanied with fully preventing the stress-enhanced SIK2 expression and cytoplasmic translocation of cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) in the hippocampus. ARN-3236 treatment also completely reversed the down-regulating effects of CSDS and CUMS on the hippocampal brain-derived neurotrophic factor (BDNF) system and neurogenesis. Moreover, we demonstrated that the hippocampal CRTC1-CREB-BDNF pathway mediated the antidepressant-like efficacy of ARN-3236. Collectively, ARN-3236 possesses strong protecting effects against chronic stress, and could be a novel antidepressant beyond monoaminergic drugs.
Highlights
As a widespread chronic medical illness affecting thoughts, mood, and physical health, depression is characterized by low mood, lack of energy, sadness, insomnia, and an inability to enjoy life (Martin et al, 2013; Ménard et al, 2016)
Conventional antidepressants used in clinical practice include selective serotonin reuptake inhibitors (SSRIs: fluoxetine, escitalopram, etc.), serotonin and norepinephrine reuptake inhibitors (SNRIs: venlafaxine, duloxetine, etc.), norepinephrine-dopamine reuptake inhibitors (NDRIs: such as bupropion) and so on (López-Muñoz and Alamo, 2009; Pereira and Hiroaki-Sato, 2018)
In 2019, we have reported that chronic stress-induced depression was accompanied by increased salt-inducible kinase 2 (SIK2) expression and decreased nuclear CRTC1 translocation and CRTC1-cyclic adenosine monophosphate response element binding protein (CREB) binding in the hippocampus (Jiang et al, 2019)
Summary
As a widespread chronic medical illness affecting thoughts, mood, and physical health, depression is characterized by low mood, lack of energy, sadness, insomnia, and an inability to enjoy life (Martin et al, 2013; Ménard et al, 2016). Conventional antidepressants used in clinical practice include selective serotonin reuptake inhibitors (SSRIs: fluoxetine, escitalopram, etc.), serotonin and norepinephrine reuptake inhibitors (SNRIs: venlafaxine, duloxetine, etc.), norepinephrine-dopamine reuptake inhibitors (NDRIs: such as bupropion) and so on (López-Muñoz and Alamo, 2009; Pereira and Hiroaki-Sato, 2018). These antidepressants are based on the monoaminergic hypothesis of depression and have shown effectiveness in the treatment of major depression. The delay in the appearance of the beneficial clinical response limits the effectiveness of these therapies (Alamo and López-Muñoz, 2009; Blier and El Mansari, 2013; Dale et al, 2015). The limited and delayed therapeutic efficacy of monoaminergic drugs has led to intensive research efforts to develop novel antidepressants
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