Abstract
Cortistatin-14 (CST-14), a recently discovered cyclic neuropeptide, can bind to all five cloned somatostatin receptors (SSTRs) and ghrelin receptor to exert its biological activities and co-exists with GABA within the cortex and hippocampus. However, the role of CST-14 in the control of depression processes is not still clarified. Here, we tested the behavioral effects of CST-14 in the in a variety of classical rodent models of depression [forced swimming test (FST), tail suspension test (TST) and novelty-suppressed feeding test]. In the models of depression, CST-14 produced antidepressant-like effects, and does not altered locomotor activity levels. And, we found that CST-14 mRNA and BDNF mRNA were significantly decreased in the hippocampus and cortex after mice exposed to stress. Further data show that i.c.v. administration of CST-14 produce rapid antidepressant effects, and does not altered locomotor activity levels. Then these antidepressant-like effects were significantly reversed by [D-Lys3]GHRP-6 (ghrelin receptor antagonist), but not c-SOM (SSTRs antagonist). Meanwhile, the effects of some neurotransmitter blockers indicates that only GABAA system, but not CRF1 receptor, α/β-adrenergic receptor, is involved in the antidepressant effect of CST-14. The effects of the mTOR inhibitor (rapamycin), the PI3K inhibitor (LY294002) and the p-ERK1/2 inhibitor (U0126) suggesting that the ERK/mTOR or PI3K/Akt/mTOR signaling pathway is not involved in the antidepressant effects of CST-14. Interestingly, intranasal administration of CST-14 led to reducing depressive-like behavior, and near-infrared fluorescent experiments showed the real-time in vivo bio-distribution in brain after intranasal infusion of Cy7.5-CST-14. Taken all together, the results of present study point to a role for CST-14 in the modulation of depression processes via the ghrelin and GABAA receptor, and suggest cortistation may represent a novel strategy for the treatment of depression disorders.Highlights: -CST-14 and BDNF mRNA are decreased in hippocampus and cortex once mice exposed to stress.-i.c.v. or intranasal administration of CST-14 produce rapid antidepressant effects.-NIR fluorescence imaging detected the brain uptake and distribution after intranasal CST-14.-Antidepressant effects of CST-14 were only related to ghrelin and GABAA system.-Co-injection of CST-14 and NPS produce antidepressant effect, and do not impair memory.
Highlights
Depression is a commonly occurring, life-threatening, and debilitating psychiatric disorder that is projected to become the second biggest contributor to the global burden of disease and disability for the year 2020, with the main symptoms of being feeling sad, anxious, hopeless or restless, and losing interest in activities (Binder and Nemeroff, 2010; Suzuki et al, 2015; Shaw et al, 2016; Tanriverdi et al, 2016; LamanMaharg et al, 2018)
We investigated the expression of CST-14 mRNA in the hippocampus and cortex of mice immediately after experiencing forced swimming test
The results revealed that these are significantly decreased in the expression of CST-14 mRNA than control, while brain-derived neurotrophic factor (BDNF) mRNA, as a positive control, is significantly decreased (Figure 1)
Summary
Depression is a commonly occurring, life-threatening, and debilitating psychiatric disorder that is projected to become the second biggest contributor to the global burden of disease and disability for the year 2020, with the main symptoms of being feeling sad, anxious, hopeless or restless, and losing interest in activities (Binder and Nemeroff, 2010; Suzuki et al, 2015; Shaw et al, 2016; Tanriverdi et al, 2016; LamanMaharg et al, 2018). Due to the various pathogenic factors involved in depression, many of the drugs fail to get remarkable effects and many patients are resistant to the treatment (Crisafulli et al, 2011; Bailey et al, 2016; Inoue et al, 2016; Roseman et al, 2017). An increasing number of articles were published during the past decade showing CST-14 moderates a broad range of physiological and pathological processes, including reduction of locomotor activity (de Lecea, 2008; Semenova et al, 2010), the production or formation of tumors (Cassoni et al, 2002), anti-inflammatory effect (Gonzalez-Rey et al, 2006; Gruber et al, 2014; Morell et al, 2014; Zhang et al, 2015a), induction of slow-wave sleep (Mendezdiaz, 2004; Gonzalez-Rey et al, 2015) and impairment of neuronal activity (Tallent et al, 2005) and inhibition of cell proliferation (Zhang et al, 2015b)
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