The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway

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.

Nuts and bolts of the salt-inducible kinases (SIKs)

“…Similar protection was observed when ARN-3236 was administered via stereotactic infusion into the hippocampus to reduce the possibility that SIK inhibition in the periphery mediates these effects [101]. Protection against CSDS or CUMS was associated with increased expression of BDNF driven by CRTC1-CREB dependent transcription [100,101].…”

“…Furthermore, the pan-SIK inhibitor ARN-3236, which crosses the bloodbrain barrier when administered by intraperitoneal injection, induced anti-depressant effects in both models of depression [101]. Similar protection was observed when ARN-3236 was administered via stereotactic infusion into the hippocampus to reduce the possibility that SIK inhibition in the periphery mediates these effects [101]. Protection against CSDS or CUMS was associated with increased expression of BDNF driven by CRTC1-CREB dependent transcription [100,101].…”

“…Moreover, the overexpression of SIK2 in the hippocampus of mice induced depressive-like behaviour, while the knock-down or KO of SIK2 in the hippocampus prevented mice from displaying such behaviour when challenged with either the CUMS or CSDS models of depression [100]. Furthermore, the pan-SIK inhibitor ARN-3236, which crosses the bloodbrain barrier when administered by intraperitoneal injection, induced anti-depressant effects in both models of depression [101]. Similar protection was observed when ARN-3236 was administered via stereotactic infusion into the hippocampus to reduce the possibility that SIK inhibition in the periphery mediates these effects [101].…”

New Insights Into the Pivotal Role of CREB-Regulated Transcription Coactivator 1 in Depression and Comorbid Obesity

“…Recently, several studies highlighted the importance of CRTC1 in stress-and inflammation-induced depressive-like behaviors, thus extending our pioneering findings on the role of CRTC1 in MDD (Davis, 2019;Jiang B. et al, 2019;Ni et al, 2019;Liu et al, 2020;Wang et al, 2020;Si et al, 2021). In a quite extensive study, the SIK2-CRTC1-CREB-BDNF pathway was proved highly instrumental in mediating chronic stressinduced depressive-like behaviors and antidepressant response in C57BL/6J mice (Jiang B. et al, 2019).…”

Aminothioneine, a product derived from golden oyster mushrooms (Pleurotus cornucopiae var. citrinopileatus), activates Ca2+ signal-mediated brain-derived neurotrophic factor expression in cultured cortical neurons

“…Although wild type huntingtin protein can interact with REST/NRSF and increase BDNF expression, mutant huntingtin, which has been found in Huntington’s disease patients, loses the ability to interact with REST/NRSF, resulting in repression of Bdnf and other REST/NRSF target genes [ 26 , 27 ]. In a chronic stress-induced depression model in mice, the levels of salt-inducible kinase 2, which is a kinase of CRTC1, was increased in the hippocampus, resulting in inhibition of CRTC1/CREB-regulated BDNF expression [ 28 ]. Therefore, enhancing Bdnf transcription in these pathological conditions may result in therapeutic effects, and agents that can induce BDNF expression in neurons may be candidate therapeutic drugs for neurological diseases.…”