Cucurbitacin B Exerts Significant Antidepressant-Like Effects in a Chronic Unpredictable Mild Stress Model of Depression: Involvement of the Hippocampal BDNF-TrkB System.

BACKGROUND: Although depression has been a serious neuropsychiatric disorder worldwide, current antidepressants used in clinical practice have various weaknesses, including delayed onset and low rates of efficacy. Recently, the development of new antidepressants from natural herbal medicine has become one of the important research hotspots. Cucurbitacin B is a natural compound widely distributed in the Cucurbitaceae and Cruciferae families and has many pharmacological activities. The present study aimed to investigate whether cucurbitacin B possess antidepressant-like effects in mice. METHODS: The antidepressant-like effects of cucurbitacin B on mice behaviors were explored using the forced swim test, tail suspension test, open field test, sucrose preference test, and a chronic unpredictable mild stress model of depression together. Then, western blotting and immunofluorescence were used to examine the effects of cucurbitacin B on the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling cascade and neurogenesis in the hippocampus of mice. Furthermore, BDNF-short hairpin RNA, K252a, and p-chlorophenylalanine methyl ester were adopted together to determine the antidepressant mechanism of cucurbitacin B. RESULTS: It was found that administration of cucurbitacin B indeed produced notable antidepressant-like effects in mice, which were accompanied with significant promotion in both the hippocampal BDNF-TrkB pathway and neurogenesis. The antidepressant mechanism of cucurbitacin B involves the hippocampal BDNF-TrkB system but not the serotonin system. CONCLUSIONS: Cucurbitacin B has the potential to be a novel antidepressant candidate.

Salt-inducible kinase 1-CREB-regulated transcription coactivator 1 signalling in the paraventricular nucleus of the hypothalamus plays a role in depression by regulating the hypothalamic-pituitary-adrenal axis.

Elucidating the molecular mechanism underlying the hyperactivity of the hypothalamic-pituitary-adrenal axis during chronic stress is critical for understanding depression and treating depression. The secretion of corticotropin-releasing hormone (CRH) from neurons in the paraventricular nucleus (PVN) of the hypothalamus is controlled by salt-inducible kinases (SIKs) and CREB-regulated transcription co-activators (CRTCs). We hypothesised that the SIK-CRTC system in the PVN might contribute to the pathogenesis of depression. Thus, the present study employed chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioural tests, virus-mediated gene transfer, enzyme-linked immunosorbent assay, western blotting, co-immunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunofluorescence to investigate this connection. Our results revealed that both CSDS and CUMS induced significant changes in SIK1-CRTC1 signalling in PVN neurons. Both genetic knockdown of SIK1 and genetic overexpression of CRTC1 in the PVN simulated chronic stress, producing a depression-like phenotype in naive mice, and the CRTC1-CREB-CRH pathway mediates the pro-depressant actions induced by SIK1 knockdown in the PVN. In contrast, both genetic overexpression of SIK1 and genetic knockdown of CRTC1 in the PVN protected against CSDS and CUMS, leading to antidepressant-like effects in mice. Moreover, stereotactic infusion of TAT-SIK1 into the PVN also produced beneficial effects against chronic stress. Furthermore, the SIK1-CRTC1 system in the PVN played a role in the antidepressant actions of fluoxetine, paroxetine, venlafaxine, and duloxetine. Collectively, SIK1 and CRTC1 in PVN neurons are closely involved in depression neurobiology, and they could be viable targets for novel antidepressants.

The salt-inducible kinases inhibitor HG-9-91-01 exhibits antidepressant-like actions in mice exposed to chronic unpredictable mild stress.

Major depressive disorder is a frequently occurring neuropsychiatric disorder throughout the world. However, the limited and delayed therapeutic efficacy of monoaminergic medications has led to intensive research efforts to develop novel antidepressants. We have previously demonstrated that hippocampal salt-inducible kinase 2 (SIK2) plays a role in the pathogenesis of depression via regulating the downstream CREB-regulated transcription coactivator 1 (CRTC1)-cAMP response element-binding protein (CREB)-brain derived neurotrophic factor (BDNF) pathway. HG-9-91-01 is a potent and selective inhibitor of salt-inducible kinases (SIKs). The present study aims to explore whether HG-9-91-01 has antidepressant-like actions in male C57BL/6J mice. The chronic unpredictable mild stress (CUMS) model of depression, various behavioral tests, western blotting, co-immunoprecipitation, immunofluorescence, stereotactic infusion, and viral-mediated genetic knockdown were used together. It was found that hippocampal infusion of HG-9-91-01 induced significant antidepressant-like effects in the CUMS model, accompanied with preventing the enhancement of CUMS on the hippocampal SIK2 expression and cytoplasmic translocation of CRTC1. HG-9-91-01 treatment also reversed the decreasing effects of CUMS on the BDNF signaling cascade and adult neurogenesis in the hippocampus. Moreover, the antidepressant-like actions of HG-9-91-01 in mice required the hippocampal CRTC1-CREB-BDNF pathway. In conclusion, HG-9-91-01 has potential of being a novel antidepressant candidate.