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Abstract
Depression is one of the foremost psychological illness, and the exact mechanism is unclear. Recent studies have reported that the pituitary adenylate cyclase-activating polypeptide (PACAP) signaling pathway is involved in the progression of depression. In the present study, we extracted crocin from the traditional Chinese medicine (TCM), Gardenia jasminoides Ellis, to evaluate its antidepressant effect and clarify the underlying mechanism. Here, we established a chronic unpredictable mild stress (CUMS) mouse model to assess whether crocin can improve depression-like behavior in an open field test (OFT), tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT). A corticosterone (CORT) model of PC12 was set up to explore the antidepressant mechanism of crocin. We pretreated PC12 cells with crocin for 1 hour and then stimulated the cells with CORT for 24 hours. Cell survival was detected by Hoechst staining and MTT assay. The expression of PACAP, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and extracellular regulated protein kinases (ERK) were analyzed by western blotting. PACAP RNAi was used to interfere with PC12 cells to downregulate the content of PACAP. The results showed that crocin (30 mg/kg) significantly reversed the decrease of body weight and elevation of serum CORT, mitigated CUMS induced depression-like behaviors of mice, and crocin (12.5 μmol/L) protected PC12 cells against CORT (200 μmol/L)-induced injury. Furthermore, crocin greatly increased the protein expression of PACAP and phosphorylation of ERK and CREB in the CORT model. PACAP RNAi cancelled the neuroprotective effect of crocin. In conclusion, these results indicated that crocin exerted an antidepressant effect via upregulating PACAP and its downstream ERK and CREB signaling pathways.
Highlights
The rapid development of society and economy can produce serious stress and adversity, which may lead to depression
Hypothalamic-pituitary-adrenal (HPA) axis is a major neuroendocrine system closely associated with stress induced depression; the activity of which was quantified with the determination of the serum level of CORT
The level of CORT was higher in the chronic unpredictable mild stress (CUMS) groups than that in the saline group (P < 0:01), but crocin and Flx reversed the elevation of serum CORT (P < 0:01, P < 0:01) (Figure 1(d))
Summary
The rapid development of society and economy can produce serious stress and adversity, which may lead to depression. Symptoms of depression include chronic low mood, cognitive impairment, and even suicide [1]. It is a leading cause of disability and a major contributor to the overall global burden of disease [2]. PACAP knockout (KO) mice showed prolonged immobility in the forced swim test (FST) [7, 8], which suggests that the PACAP signal pathway may be involved in depression pathogenesis. 180 min maternal deprivation of PACAP heterozygous mice on CD1 background upon CVMS (chronic variable mild stress) may be used as a reliable model for major depression [9].
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