Hippocampal pituitary adenylate cyclase-activating polypeptide mediates rapid antidepressant-like effects of Yueju pill.

Yueju pill, a classic Chinese Medicine formulated, was recently found to produce rapid antidepressant-like effects in a PKA-CREB signaling-dependent manner. In our study, we found that the Yueju pill induced a remarkable increase in PACAP. The intracerebroventricular injection of PACAP agonist induced a rapid antidepressant-like effect; conversely, the intrahippocampal infusion of a PACAP antagonist reversed the antidepressant response of the Yueju pill. Mice with hippocampal PACAP knockdown via viral-mediated RNAi displayed depression-like behavior. PACAP knockdown also blunted the antidepressant effect of the Yueju pill. PACAP knockdown resulted in down-regulated CREB and expression of the synaptic protein PSD95 at both baselines and after administration of the Yueju pill. However, administration of the Yueju pill in the knockdown mice promoted PACAP and PKA levels. Chronically stressed mice showed deficient hippocampal PACAP-PKA-CREB signaling and depression-like behavior, which were reversed by a single dose of the Yueju pill. In this study, we demonstrated that the up-regulation of PACAP induced activating of PKA-CREB signaling would play a part in the rapid antidepressant-like effects of the Yueju pill. We also identified iridoids fraction of Gardenia jasminoides Ellis (GJ-IF), a vital component of the Yueju pill, was identified to recapitulate rapid antidepressant-like behavior through increased hippocampal PACAP expression of the Yueju pill. The promotion of hippocampal PACAP may collectively represent a novel mechanism of rapid antidepressant-like effect.

Quercitrin Rapidly Alleviated Depression-like Behaviors in Lipopolysaccharide-Treated Mice: The Involvement of PI3K/AKT/NF-κB Signaling Suppression and CREB/BDNF Signaling Restoration in the Hippocampus.

Quercitrin (Qc) is a well-known flavonoid compound that exerts anti-inflammation effects on various diseases. The present study aimed to investigate the antidepressant-like response of Qc and its underlying mechanisms concerning neuroinflammation and neuroplasticity in mice with lipopolysaccharide (LPS)-induced depression-like behaviors. The results showed a single dose of Qc (10 mg/kg) produced an antidepressant-like effect at 2 h postadministration and lasted for at least 3 days. The expressions of neuroplasticity signaling molecules of pCREB/BDNF/PSD95/Synapsin1 were upregulated at 2 h, and ERK signaling was upregulated for 3 days in the hippocampus after a single administration of Oc or ketamine. A 5-day treatment of LPS led to depression-like behaviors, including reduced sucrose preference and increased immobility in the tail suspension test or forced swim test, which were all reversed by a single dose of Qc. In LPS-treated mice, Qc reduced the levels of inflammation-related factors including IL-10, IL-1ß, and TNF-α in serum, as well as the activations of PI3K/AKT/NF-κB and MEK/ERK pathways in the hippocampus. Moreover, Qc restored the expressions of pCREB/BDNF/PSD95/Synapsin1 signaling in the hippocampus that were impaired by LPS. LY294002, a PI3K inhibitor, but not PD98059, a MEK inhibitor, produced effects similar to Qc. LY294002 also restored the expressions of pCREB/BDNF/PSD95/Synapsin1 signaling in the hippocampus impaired by LPS. Additionally, subeffective doses of Qc and LY294002 induced behavioral and molecular synergism. Together, the depression-like behaviors in LPS-treated mice were alleviated by a single dose of Qc likely via inhibition of the activations PI3K/AKT/NF-κB inflammation signaling and subsequent improvement of neuroplasticity.

Latent Sex Differences in CaMKII-nNOS Signaling That Underlie Antidepressant-Like Effects of Yueju-Ganmaidazao Decoction in the Hippocampus.

Previous studies have demonstrated that Yueju-Ganmaidazao (YG) decoction induces rapid antidepressant-like effects, and the antidepressant response is mostly dependent on the suppression of nitric oxide-cyclic guanosine monophosphate signaling in male mice. This study aimed to investigate the sex difference mediated by calcium/calmodulin-dependent protein kinase II (CaMKII)-neuronal nitric oxide synthase (nNOS) signaling involved in the antidepressant-like effect of YG in mice. We found that the immobility times in the tail suspension test (TST) were found to be decreased after the single injection of YG in male and female mice with the same dosage. Additionally, chronic administration for 4 days of subthreshold dosage of YG and escitalopram (ES) also significantly decreased the immobility time in mice of both sexes. Chronic subthreshold dosage of YG and ES in LPS-treated mice and in chronic unpredictable stress (CUS) mice both decreased the immobility time, which was increased by stress. Meanwhile, in CUS-treated mice, sucrose preference test, forced swimming test, and open field test were applied to further confirm the antidepressant-like effects of YG and ES. Moreover, CUS significantly decreased the expression of nNOS and CaMKII, and both YG and ES could enhance the expression in the hippocampus of female mice, which was opposite to that in male mice, while endothelial nitric oxide synthase expression was not affected by stress or drug treatment neither in male mice nor in female mice. Finally, subthreshold dosage of YG combined with 7-nitroindazole (nNOS inhibitor) induced the antidepressant-like effects both in female and in male mice, while the single use of YG or 7-NI did not display any effect. However, pretreatment with KN-93 (CaMKII inhibitor) only blocked the antidepressant-like effect of high-dosage YG in female mice. Meanwhile, in CUS mice, chronic stress caused NR1 overexpression and inhibited cAMP response element binding protein action, which were both reversed by YG and ES in male and female mice, implying that YG and ES produced the same antidepressant-like effect in mice of both sexes. The study revealed that chronic treatment with a subthreshold dose of YG also produced antidepressant-like effects in female mice, and these effects depended on the regulation of the CaMKII-nNOS signaling pathway.

Alisma orientalis Beverage Treats Atherosclerosis by Regulating Gut Microbiota in ApoE-/- Mice.

BACKGROUND: Alisma orientalis beverage (AOB) is a Chinese traditional medicine formulated with a diversity of medicinal plants and used for treating metabolic syndrome and atherosclerosis (AS) since time ago. Given the current limited biological research on AOB, the mechanism by which AOB treats AS is unknown. This study investigats the role of AOB-induced gut microbiota regulation in the expansion of AS. METHODS: We established an AS model in male apolipoprotein E-deficient (ApoE-/-) mice that are fed with a high-fat diet (HFD), treated with numerous interventions, and evaluated the inflammatory cytokines and serum biochemical indices. The root of the aorta was stained with oil red O, and the proportion of the lesion area was quantified. Trimethylamine N-oxide (TMAO) and trimethylamine (TMA) levels in serum were evaluated through liquid chromatography with mass spectrometry. Flavin-containing monooxygenase 3 (FMO3) liver protein expression was assessed by Western blotting. 16S rDNA sequencing technique was adopted to establish the changes in the microbiota structure. RESULTS: After 8 weeks of HFD feeding, an inflammatory cytokine, and AS development expression were significantly decreased in mice treated with AOB; the same parameters in the mice treated with the antibiotics cocktail did not change. In the gut microbiota study, mice treated with AOB had a markedly different gut microbiota than the HFD-fed mice. Additionally, AOB also decreased serum TMAO and hepatic FMO3 expression. CONCLUSION: The antiatherosclerotic effects of AOB were found associated with changes in the content of gut microbiota and a reduction in TMAO, a gut microbiota metabolite, suggesting that AOB has potential therapeutic value in the treatment of AS.

Crocin Reverses Depression-Like Behavior in Parkinson Disease Mice via VTA-mPFC Pathway.

Depression is a common non-motor symptom in patients with Parkinson's disease (PD) and difficult to treat. Crocin is a natural multipotential neuroprotective compound that has been shown to elicit antidepressant activity and is promising for the therapy of neuropsychological diseases. Here, we investigated the therapeutic effect of crocin in a mouse model of Parkinson's disease depression (PDD) and clarified the underlying mechanism. We prepared 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced subacute mouse model of PD, and found that around 60% of the model mice showed depression-like behavior, using the forced swimming test (FST). A regime of 10-day treatment of crocin alleviated the PDD symptoms. The crocin reduced the structural damage in soma volume and axon length of neurons and inhibited their spontaneous discharge in dopaminergic (DA) neurons in the ventral tegmental area (VTA). Notably, the MPTP-treated mice showed the decrease in the critical signaling for synaptic plasticity, including the proteins of PSD-95, synapsin-1, and GluR-1, in the medial prefrontal cortex (mPFC) where it receives efferent from VTA and regulates depression-like behavior. However, crocin treatment rescued the defect of the mammalian target of rapamycin (mTOR) signaling in PDD mice. Furthermore, the antidepressant action of crocin was blunted after blockade of mTOR signaling with the antagonist rapamycin. In conclusion, our study demonstrated that crocin protected the DA projection neurons in the VTA through activating mTOR, which subsequently improved the neural synaptic plasticity of mPFC, and ameliorated depression-like behavior in PD mice.

Yueju-Ganmaidazao Decoction confers rapid antidepressant-like effects and the involvement of suppression of NMDA/NO/cGMP signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Yueju-Ganmaidazao Decoction (YG) is a multiherbal medicine prescribed for treatment of mood disorder, consisting of two classical traditional Chinese herbal medicine Yueju and Ganmaidazao. Yueju and Ganmaidazao both are used for depression treatment. The combined decoction of Yueju and Ganmaidazao is prescribed to achieve optimal clinical outcomes by dealing with different symptoms of depression. Recent studies indicated ethanol extract of Yueju was capable to confer rapid antidepressant-like response. The antidepressant activity of YG decoction with fast-onset feature remains to be investigated. AIM OF THE STUDY: Rapid and safe antidepressant treatment is urgently needed. This study aimed to assess the rapid antidepressant-like activity of YG and the underlying mechanism, focusing on NMDA/NO/cGMP signaling. MATERIALS AND METHODS: The optimal doses for immediate and persistent antidepressant-like response were first screened using tail suspension test (TST) and forced swimming test (FST) post a single administration of YG. The rapid action was further confirmed by using the chronic mild stress (CMS) and learned helplessness (LH) paradigms. The expressions of NMDA receptor subunits were evaluated post stress and YG. The contributions of NMDA, NO, and cGMP signaling to the antidepressant effect of YG were investigated systematically using pharmacological interventions. RESULTS: The optimal dose for immediate and persistent antidepressant potential, evidenced with reduced immobility times in TST or FST from 30 min to 7 days, was determined. The rapid antidepressant-like effect was confirmed in CMS and LH paradigms, including instant normalization of sucrose preference behavior. The expression of NMDA subunit NR1 in the hippocampus was reduced from 30 min to 5 days post YG. In animals subjected to CMS and LH, hippocampal NR1 expression increased, reversed by YG. YG's antidepressant-like effect was blunted by pretreatment with the agonists along the signalings including NMDA (75 mg/kg), L-arginine (750 mg/kg) and sildenafil (5 mg/kg) in TST or FST. Conversely, administration of subeffective dose of individual antagonists, including MK-801 (0.05 mg/kg), 7-nitroindazole (30 mg/kg), methylene blue (10 mg/kg), in combination with a subeffective dose of YG, elicited antidepressant effects. CONCLUSION: YG conferred rapid antidepressant-like effects, and the antidepressant response was essentially dependent on suppression of NMDA/NO/cGMP signaling.

Methyl jasmonate promote protostane triterpenes accumulation by up-regulating the expression of squalene epoxidases in Alisma orientale.

Protostane triterpenes, which are found in Alisma orientale, are tetracyclic triterpenes with distinctive pharmacological activities. The natural distribution of protostane triterpenes is limited mainly to members of the botanical family Alismataceae. Squalene epoxidase (SE) is the key rate-limiting enzyme in triterpene biosynthesis. In this study, we report the characterization of two SEs from A. orientale. AoSE1 and AoSE2 were expressed as fusion proteins in E. coli, and the purified proteins were used in functional research. In vitro enzyme assays showed that AoSE1 and AoSE2 catalyze the formation of oxidosqualene from squalene. Immunoassays revealed that the tubers contain the highest levels of AoSE1 and AoSE2. After MeJA induction, which is the main elicitor of triterpene biosynthesis, the contents of 2,3-oxidosqualene and alisol B 23-acetate increased by 1.96- and 2.53-fold, respectively. In addition, the expression of both AoSE proteins was significantly increased at four days after MeJA treatment. The contents of 2,3-oxidosqualene and alisol B 23-acetate were also positively correlated with AoSEs expression at different times after MeJA treatment. These results suggest that AoSE1 and AoSE2 are the key regulatory points in protostane triterpenes biosynthesis, and that MeJA regulates the biosynthesis of these compounds by increasing the expression of AoSE1 and AoSE2.

NMDA receptors and L-arginine/nitric oxide/cyclic guanosine monophosphate pathway contribute to the antidepressant-like effect of Yueju pill in mice.

The present study aims to evaluate the involvement of N-methyl-d-aspartate receptor and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) system in antidepressant-like effects of Yueju pill (YJ), a Chinese herbal medicine. The immobility time in tail suspension test (TST) and forced swim test (FST) was used to assess the antidepressant effects. Prior administration of L-arginine (750 mg/kg, intraperitoneal [i.p.]), a NO synthase substrate that enhances NO signaling or sildenafil (5 mg/kg, i.p.), a phosphodiesterase 5 inhibitor that enhances cGMP, blunted the antidepressant-like activity of YJ (2.7 g/kg, i.g.). Co-treatment of ineffective dose of YJ (1.35 g/kg, i.g.) with one of the reagents that suppress the NO/cGMP signaling, including methylene blue (10 mg/kg, i.p.), an inhibitor of NO synthase; 7-NI (7-nitroinidazole, 30 mg/kg, i.p.), an nNOS specific inhibitor; L-NAME (10 mg/kg, i.p.), a non-specific inhibitor of NO synthase; and MK-801 (0.05 mg/kg, i.p.), an NMDA receptor antagonist, reduced the immobility time in TST and FST, compared with those in vehicle or single drug treatment groups. Neither above drugs alone or co-administrated with YJ affected locomotor activity or anxiety behavior in open field test. Thus, our results suggest that the antidepressant-like action of YJ may depend on the inhibition of NMDA/NO/cGMP pathway.

Immediate and persistent antidepressant-like effects of Chaihu-jia-Longgu-Muli-tang are associated with instantly up-regulated BDNF in the hippocampus of mice.

Conventional antidepressants have a disadvantage in delayed onset of efficacy. Here, we aimed to evaluate the immediate and persistent antidepressant-like action of a classic herbal medicine Chaihu-jia-Longgu-Muli decoction (CLM) as well as the action of CLM on hippocampal brain-derived neurotrophic factor (BDNF) over time. CLM consists of Xiaochaihu decoction (XchD), Longgu-Muli (LM) and several other herbs. The contribution of constituent herbal formula XchD and other parts of CLM was also assessed. Following a single dose of CLM, tail suspension test (TST), forced swim test (FST), and novelty-suppressed feeding test (NSF) were performed. The antidepressant activity of XchD, its interaction with LM or remaining parts of CLM was also examined after a single administration. BDNF expression in the hippocampus was examined at 30 min and 24 hr post a single CLM. A single administration of half of clinical dose of CLM elicited antidepressant effects at TST 30 min post administration, and lasted for 72 hr. Furthermore, CLM also reduced the latency to eat in NSF test. A single proportional dose of XchD induced antidepressant effects at 30 min and lasted for 48 hr, whereas the effect lasted for 72 hr when combined with either LM or the remaining parts of CLM. BDNF expression increased at 30 min and persisted at least for 24 hr after a single dose of CLM. The results support that Chaihu-jia-Longgu-Muli decoction was capable to immediately and enduringly elicit antidepressant activity via enhancement of hippocampal BDNF expression, in which the constituent Xiaochaihu decoction played the primary role.

Full genetic analysis for genome-wide association study of Fangji: a powerful approach for effectively dissecting the molecular architecture of personalized traditional Chinese medicine.

Elucidation of the systems biology foundation underlying the effect of Fangji, which are multi-herbal traditional Chinese medicine (TCM) formulas, is one of the major aims in the field. The numerous bioactive ingredients of a Fangji deal with the multiple targets of a complex disease, which is influenced by a number of genes and their interactions with the environment. Genome-wide association study (GWAS) is an unbiased approach for dissecting the genetic variants underlying complex diseases and individual response to a given treatment. GWAS has great potential for the study of systems biology from the point of view of genomics, but the capacity using current analysis models is largely handicapped, as evidenced by missing heritability. Recent development of a full genetic model, in which gene-gene interactions (dominance and epistasis) and gene-environment interactions are all considered, has addressed these problems. This approach has been demonstrated to substantially increase model power, remarkably improving the detection of association of GWAS and the construction of the molecular architecture. This analysis does not require a very large sample size, which is often difficult to meet for a GWAS of treatment response. Furthermore, this analysis can integrate other omic information and allow for variations of Fangji, which is very promising for Fangjiomic study and detection of the sophisticated molecular architecture of the function of Fangji, as well as for the delineation of the systems biology of personalized medicine in TCM in an unbiased and comprehensive manner.

Involvement of NMDA-AKT-mTOR Signaling in Rapid Antidepressant-Like Activity of Chaihu-jia-Longgu-Muli-tang on Olfactory Bulbectomized Mice.

Background: Fast-onset antidepressants are urgently needed. Chaihu-jia-Longgu-Muli-tang (CLM), a classic Chinese herbal medicine, has been used for antidepressant treatment with long history. Olfactory bulbectomization (OB) model is validated for identification of rapid antidepressant efficacy. Here we used OB model for investigating the rapid onset activity of CLM in mice, and also tested the involvement of prefrontal Akt-mTOR and associated AMPA/NMDA receptors as well as hippocampal BDNF in the rapid antidepressant-like effect of CLM. Methods: The OB model was first characterized with depression-like behaviors and the time course changes of the behaviors. The fast onset of antidepressant effect of CLM was evaluated using sucrose preference test, tail suspension test and forced swim test in OB mice after a single administration. The expression of synaptic proteins of AMPA and NMDA subunits as well as Akt/mTOR signaling in the prefrontal cortex, and hippocampal BDNF was evaluated with the immunoblotting method. Results: A single dose of CLM significantly improved the deficiency in the sucrose preference and decreased the immobility time in the tail suspension test in OB mice. In the prefrontal cortex (PFC) in OB mice, there was lower expression level of the AMPA receptor subunit GluR1, rescued by a single dose of CLM. Additionally, the expression of NMDA subunit NR1 was up-regulated in OB mice, whereas mTOR and its upstream Akt signalings were both down-regulated. These deficiencies were reversed by a single dose of CLM. The CLM treatment also attenuated the expressions of NMDA receptor subunits NR2A and NR2B, which did not change in OB mice. In the hippocampus, expressions of GluR1 and brain derived neurotrophic factor (BDNF) were both up-regulated in OB mice, although CLM increased GluR1, but not BDNF. Conclusion: CLM elicited rapid antidepressant-like effects in the OB model mice, and CLM reversal of the abnormality in PFC expression of AMPA and NMDA receptors and associated Akt-mTOR signaling may underlie the effects.

An association study revealed substantial effects of dominance, epistasis and substance dependence co-morbidity on alcohol dependence symptom count.

Alcohol dependence is a complex disease involving polygenes, environment and their interactions. Inadequate consideration of these interactions may have hampered the progress on genome-wide association studies of alcohol dependence. By using the dataset of the Study of Addiction: Genetics and Environment with 3838 subjects, we conducted a genome-wide association studies of alcohol dependence symptom count (ADSC) with a full genetic model considering additive, dominance, epistasis and their interactions with ethnicity, as well as conditions of co-morbid substance dependence. Twenty quantitative trait single nucleotide polymorphisms (QTSs) showed highly significant associations with ADSC, including four previously reported genes (ADH1C, PKNOX2, CPE and KCNB2) and the reported intergenic rs1363605, supporting the overall validity of the analysis. Two QTSs within or near ADH1C showed very strong association in a dominance inheritance mode and increased the phenotype value of ADSC when the effect of co-morbid opiate or marijuana dependence was controlled. Highly significant association was also identified in variants within four novel genes (RGS6, FMN1, NRM and BPTF), two non-coding RNA and two epistasis loci. QTS rs7616413, located near PTPRG encoding a protein tyrosine phosphatase receptor, interacted with rs10090742 within ANGPT1 encoding a protein tyrosine phosphatase in an additive × additive or dominance × additive manner. The detected QTSs contributed to about 20 percent of total heritability, in which dominance and epistasis effects accounted for over 50 percent. These results demonstrated that perturbations arising from gene-gene interaction and conditions of co-morbidity substantially influence the genetic architecture of complex trait.

Transgenerational impairment of hippocampal Akt-mTOR signaling and behavioral deficits in the offspring of mice that experience postpartum depression-like illness.

Postpartum depression (PPD) has adverse effects on offspring and increases their vulnerability to psychiatric disorders such as depression. Akt-mTOR signaling in the hippocampus is implicated in depression but its role in the behavioral deficits in PPD offspring remains unknown. By using a prepregnancy stress model of PPD in which Balb/c females that experience chronic stress before pregnancy show long-lasting PPD-like behaviors, we tested depression-like behaviors in PPD offspring (PPD-F1) at juvenile and adult ages as well as in the second generation (PPD-F2) produced by cross of male PPD-F1 with naïve females. Hippocampal Akt-mTOR signaling was examined in the F1 and F2 generations of PPD, as well as in PPD-F1 mice treated with a single dose of the antidepressant ketamine. PPD-F1 showed depression-like behaviors at juvenile and adult stages, evidenced by reduced sucrose preference (SP), increased immobility time in the forced swim test (FST), and a longer latency to feed and reduced food consumption in the novelty suppressed feeding (NSF) test. PPD-F1 mice showed Akt-mTOR signaling deficiency in the hippocampus, with down-regulated expression of p-Akt, p-mTOR and p-p70S6K. A single dose of ketamine reversed the behavior deficits and the impairment in Akt-mTOR signaling in PPD-F1. Furthermore, the PPD-F2 mice remained deficient in the SP and NSF test and hippocampal Akt-mTOR signaling, although the performance in FST was normal. The present study demonstrated both long-term and transgenerational effects of PPD on the depression-like behaviors of offspring, and suggested impaired Akt-mTOR signaling may play a part.

Chronic stress prior to pregnancy potentiated long-lasting postpartum depressive-like behavior, regulated by Akt-mTOR signaling in the hippocampus.

Postpartum depression (PPD) affects over 10% of new mothers and adversely impacts the health of offspring. One of the greatest risk factors for PPD is prepregnancy stress but the underlying biological mechanism is unknown. Here we constructed an animal model which recapitulated prepregnancy stress induced PPD and tested the role of Akt-mTOR signaling in the hippocampus. Female virgin Balb/c mice received chronic restraint stress, followed by co-housing with a normal male mouse. We found that the chronic stress led to a transient depressive-like condition that disappeared within two weeks. However, prepregnantly stressed females developed long-term postpartum depressive-like (PPD-like) symptoms as indicated by deficient performance in tests of sucrose preference, forced swim, and novelty-suppressed feeding. Chronic stress induced transient decrease in Akt-mTOR signaling and altered expressions of glutamate receptor subunits NR1 and GluR1, in contrast to long-term deficits in Akt-mTOR signaling, GluR1/NR1 ratio, and hippocampal neurogenesis in PPD-like mice. Acute ketamine improved the molecular signaling abnormality, and reversed the behavioral deficits in PPD-like mice in a rapid and persistent manner, in contrast to ineffectiveness by chronic fluoxetine treatment. Taken together, we find that chronic prepregnancy stress potentiates a long-term PPD, in which Akt-mTOR signaling may play a crucial role.

Crocetin ester improves myocardial ischemia via Rho/ROCK/NF-κB pathway.

Crocetin ester (CE) is the active ingredient of Crocus sativus L. stigmas and Gardenia jasminoides Ellis fruit. The main purpose of the present study was to investigate the protective effect of CE on isoproterenol (ISO)-induced acute myocardial ischemia (AMI) through Rho/ROCK/NF-κB pathway and explore its underlying mechanism. Administration of CE (25 and 50mg/kg) could significantly reduce the serum contents of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6). In addition, pretreatment with CE attenuated the contents of creatine kinase (CK), malondialdehyde (MDA) and the activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD) in serum. Treatment with CE also improved the histopathological alteration and decreased the ST elevation. Furthermore, CE could ameliorate the cardiac expressions of Cu, Zn-superoxide dismutase (SOD1), MDA5, Rho, ROCK, p-IκB and p-NF-κBp65 in ISO-induced rats. It was assumed that CE might be a new therapeutic candidate for the treatment of AMI possibly through the inhibition of Rho/ROCK/NF-κB pathway.

[Effect of Postpartum Depression on Adolescent Depression of Mice Offspring].

OBJECTIVE: To study the effect of postpartum depression (PPD) on adolescent depression of mice offspring. METHODS: Totally 48 Balb/c female mice were equally randomized into control group and stress group. Control group was not given any stress, whereas stress group were given chronic stress: constraining (6 h/d) combined with light stimulation for 24 hours (twice a week). The stress group was divided into 3 groups to measue the animals' behaviors immediately after modeling, three weeks after modeling, and three weeks after delivery to test whether the PPD models were successfully constructed. The first generation (F1) of normal mothers and PPD-born F1 were as follows: control group (CTL-F1) and PPD offspring group (PPD-F1). The 3-4-week-old male CTL-F1 and PPD-F1 mice (n=8 each) were weighed, and received sucrose preference test, forced swimming test, and novelty-supressed feeding test to measure the depression-like behaviors. RESULTS: The 3-and 4-week-old PPD-F1 had significantly lower body mass than CTL-F1 (P=0.000, P=0.002). Also, the sucrose preference significantly decreased (P=0.000), the forced swimming immobility time significantly increased (P=0.001), the latency to feed significantly increased (P=0.000), while food intake significantly decreased (P=0.005). CONCLUSION: PPD offspring may be more susceptible to depression,with a possible eary onset in adolescence.

PKA-CREB-BDNF signaling regulated long lasting antidepressant activities of Yueju but not ketamine.

Yueju confers antidepressant effects in a rapid and long-lasting manner, similar to ketamine. CREB (cAMP-response element binding protein) signaling is implicated in depression pathology and antidepressant responses. However, the role of CREB and associated brain derived neurotrophic factor (BDNF) signaling in rapid and long-lasting antidepressant effects remains unclear. Here, we demonstrated that ICR and Kunming strain mice conferred antidepressant responses lasting for 1 and 5 days, respectively, following a single dose of Yueju. One day post Yueju in Kunming but not ICR strain mice, expression of total and phosphorylated CREB, as well as the CREB signaling activator, PKA (protein kinase A) was up-regulated in the hippocampus. Although BDNF gene expression increased at 3 hours in both strains, it remained up-regulated at 1 day only in Kunming mice. Ketamine showed similar strain-dependent behavioral effects. However, blockade of PKA/CREB signaling blunted the antidepressant effects and reversed the up-regulation of BDNF gene expression by Yueju, but not ketamine. Conversely, blockade of mammalian target of rapamycin signaling led to opposite effects. Taken altogether, prolonged transcriptional up-regulation of hippocampal BDNF may account for the stain-dependent enduring antidepressant responses to Yueju and ketamine, but it was mediated via PKA/CREB pathway only for Yueju.

Instant and Persistent Antidepressant Response of Gardenia Yellow Pigment Is Associated with Acute Protein Synthesis and Delayed Upregulation of BDNF Expression in the Hippocampus.

Gardenia yellow pigment (GYP) is a collection of compounds with shared structure of crocin, which confers antidepressant activity. GYP is remarkably enriched in Gardenia jasminoides Ellis, implicated in rapid antidepressant effects that are exerted through enhanced neuroplasticity. This study aims to investigate the rapid antidepressant-like activity of GYP and its underlying mechanism. After the optimal dose was determined, antidepressant responses in tail suspension test or forced swim test were monitored at 30 min, 1 day, 3 days, and 7 days post a single GYP administration. Rapid antidepressant potential was tested using learned helplessness paradigm. The expression of proteins involved in hippocampal neuroplasticity was determined. The effect of blockade of protein synthesis on GYP's antidepressant response was examined. Antidepressant response was detected at 30 min, and lasted for at least 3 days post a single administration of GYP. A single administration of GYP also reversed the deficits in learned helplessness test. Thirty minutes post GYP administration, ERK signaling was activated, and its downstream effector phosphorylated eukaryotic elongation factor 2 was inhibited, contributing to increased protein translation. Expression of synaptic proteins GluR1 and synapsin 1 was upregulated. Blockade of protein synthesis with anisomycin blunted the immediate antidepressant response of GYP. CREB signaling and BDNF expression were upregulated at 24 h, but not at 30 min. In conclusion, GYP-induced immediate antidepressant response was dependent on synthesis of proteins, including synaptic proteins. This was followed by enhanced expression of CREB and BDNF, which likely mediated the persistent antidepressant responses.

Paeonol attenuates lipopolysaccharide-induced depressive-like behavior in mice.

The present study was designed to detect the anti-depressant effects of paeonol and the possible mechanisms in the lipopolysaccharide-induced depressive-like behavior. Open-field test(OFT), tail suspension test(TST) and forced swimming test(FST) were used to evaluate the behavioral activity. The contents of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in mice hippocampus were determined by HPLC-ECD. Serum interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α levels were evaluated by enzyme-linked immunosorbent assay (ELISA). Our results showed that LPS significantly decreased the levels of 5-HT and NE in the hippocampus. LPS also reduced open-field activity, as well as increased immobility duration in FST and TST. Paeonol administration could effectively reverse the alterations in the concentrations of 5-HT, NE and reduce the IL-6 and TNF-α levels. Moreover, paeonol effectively downregulated brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and Nuclear factor-κB (NF-κB) in hippocampal. In conclusion, paeonol administration exhibited significant antidepressant-like effects in mice with LPS-induced depression.

Liquiritigenin reverses depression-like behavior in unpredictable chronic mild stress-induced mice by regulating PI3K/Akt/mTOR mediated BDNF/TrkB pathway.

Major depression is a common long-lasting or recurrent psychiatric disease with high lifetime prevalence and high incidence of suicide. The main purpose of the current study was to verify whether liquiritigenin conferred an antidepressant-like effect on the depressive mouse model established by unpredictable chronic mild stress (UCMS) and explore its possible mechanism. The results of depression-related behaviors including sucrose preference test (SPT), open field test (OFT), forced swimming test (FST) and tail suspension test (TST) indicated that both liquiritigenin (7.5mg/kg, 15mg/kg) and fluoxetine (20mg/kg) dramatically improved the depression symptoms. Enzyme-linked immunosorbent assay (ELISA) revealed that treatment with liquiritigenin significantly reduced the concentrations of pro-inflammatory cytokines including interleukin (IL)-6, IL-1ß and tumor necrosis factor (TNF)-α in serum and hippocampus. Compared with the UCMS group, the administrations of liquiritigenin, increased levels of superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and decreased Malondialdehyde (MDA) content. Meanwhile, glucocorticoids (GC) content was reduced in the liquiritigenin group, which suggested that liquiritigenin exhibiting the ameliorative effect on activated hypothalamic-pituitary-adrenal (HPA) axis stimulated with UCMS. Mice treated with liquiritigenin showed restored levels of neurotransmitter norepinephrine (NE) and serotonin (5-HT). Western blot analysis displayed up-regulated expressions of p-phosphatidylinositol 3-kinase (PI3K), p-Akt, p- mammalian target of rapamycin (mTOR), p-tropomyosin-related kinase B (TrkB), brain-derived neurotrophic factor (BDNF). Thus, it was supposed that liquiritigenin might be useful for the treatment of chronic depression possibly through PI3K/Akt/mTOR mediated BDNF/TrkB pathway.