Wenda Xue

Involvement of normalized NMDA receptor and mTOR-related signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice

Yueju, a Traditional Chinese Medicine formula, exhibited fast-onset antidepressant responses similar to ketamine. This study focused on assessing the rapid and persistent antidepressant efficacy of Yueju and ketamine in chronically stressed mice and its association with alternations in prefrontal N-methyl-D-aspartate (NMDA) receptor and mammalian target of rapamycin (mTOR)-related activity. Chronic mild stress (CMS) led to deficits in sucrose preference test (SPT), forced swim test, tail suspension test, and novelty-suppressed feeding test, which were improved differently by acute Yueju or ketamine administration. The improvement in SPT started as soon as 2 hours post Yueju and ketamine but lasted for 6 days only by Yueju. Body weight was regained by Yueju more than ketamine at post-drug administration day (PAD) 6. CMS decreased phosphorylation of the mTOR effectors 4E-BP1 and p70S6K, their upstream regulators ERK and Akt, and downstream targets including synaptic protein GluR1. Yueju or ketamine reversed these changes at PAD 2, but only Yueju reversed phosphor-Akt at PAD 6. CMS selectively and lastingly increased NMDA receptor subunit NR1 expression, which was reversed by ketamine or Yueju at PAD 2 but only by Yueju at PAD 6. These findings suggest that NR1 and Akt/mTOR signaling are important therapeutic targets for depression.

Yueju Pill Rapidly Induces Antidepressant-Like Effects and Acutely Enhances BDNF Expression in Mouse Brain

The traditional antidepressants have a major disadvantage in delayed onset of efficacy, and the emerging fast-acting antidepressant ketamine has adverse behavioral and neurotoxic effects. Yueju pill, an herb medicine formulated eight hundred years ago by Doctor Zhu Danxi, has been popularly prescribed in China for alleviation of depression-like symptoms. Although several clinical outcome studies reported the relative short onset of antidepressant effects of Yueju, this has not been scientifically investigated. We, therefore, examined the rapid antidepressant effect of Yueju in mice and tested the underlying molecular mechanisms. We found that acute administration of ethanol extract of Yueju rapidly attenuated depressive-like symptoms in learned helpless paradigm, and the antidepressant-like effects were sustained for at least 24 hours in tail suspension test in ICR mice. Additionally, Yueju, like ketamine, rapidly increased the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, whereas the BDNF mRNA expression remained unaltered. Yueju rapidly reduced the phosphorylation of eukaryotic elongation factor 2 (eEF2), leading to desuppression of BDNF synthesis. Unlike ketamine, both the BDNF expression and eEF2 phosphorylation were revered at 24 hours after Yueju administration. This study is the first to demonstrate the rapid antidepressant effects of an herb medicine, offering an opportunity to improve therapy of 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-1β 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.

Rapid Antidepressant Activity of Ethanol Extract of Gardenia jasminoides Ellis Is Associated with Upregulation of BDNF Expression in the Hippocampus

Ethanol extract of Yueju pill, a Traditional Chinese Medicine herbal formula widely used to treat mood disorders, demonstrates rapid antidepressant effects similar to ketamine, likely via instant enhancement of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Here we investigated ethanol extracts of the constituent herbs of Yueju responsible for rapid antidepressant effects. Screening with tail suspension test in Kunming mice at 24 hours after a single administration of five individual constituent herbs of Yueju, we found that only Gardenia jasminoides Ellis (GJ) showed a significant effect. The antidepressant response started at 2 hours after GJ administration. Similar to Yueju and ketamine, a single administration of GJ significantly reduced the number of escape failures in the learned helplessness test. Furthermore, GJ decreased latency of food consumption in the novelty suppressed-feeding test. Additionally, starting from 2 hours and continuing for over 20 hours after GJ administration, BDNF expression in the hippocampus was upregulated, temporally linked with the antidepressant response. These findings suggest that GJ has rapid antidepressant effects, which are associated with the elevated expression of BDNF in the hippocampus. In Yueju formula, Yue represents GJ, as thus our study demonstrates the primary role of GJ in rapid antidepressant efficacy of Yueju.

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.

Optimization of Supercritical Fluid Extraction of Oil from the Fruit of Gardenia jasminoides and Its Antidepressant Activity

A response surface methodology was applied to optimize the variables affecting the supercritical fluid carbon dioxide extraction of oil from the fruit of Gardenia jasminoides using the Box–Behnken design. The optimum extraction parameters were an extraction temperature of 49.94 °C, an extraction pressure of 29.89 MPa and an extraction time of 93.82 min. Through a GC/MS analysis, we revealed 16 major components of the oil extract, which showed potent antidepressant effects in both of two behavior despair models in mice: tail suspension test and forced swimming test. Our results suggest that the oil extract of Gardenia jasminoides prepared using the supercritical fluid carbon dioxide extraction may contain effective constituents to be used for depression therapy.

A role of Yueju in fast-onset antidepressant action on major depressive disorder and serum BDNF expression: a randomly double-blind, fluoxetine-adjunct, placebo-controlled, pilot clinical study

Introduction Conventional antidepressants, including fluoxetine, have a major disadvantage in delayed onset of efficacy. Yueju, an herbal medicine used to treat mood disorders was recently found to exhibit rapid antidepressant effects. The present study was conducted to evaluate the role of Yueju in rapidly acting on major depressive disorder (MDD). Methods Participants were MDD patients with scores of 24-item Hamilton Depression Rating Scale (HDRS-24) ≥20 and without history of antidepressant use. They randomly received daily oral doses of Yueju (23 g/day) plus fluoxetine (20 mg/day) (experimental group) or placebo plus fluoxetine (control group) for 7 days. HDRS-24 was used as the primary outcome measurement at baseline, and on days 1, 3, 5, and 7. Concentrations of serum brain-derived neurotrophic factor (BDNF) were assessed at baseline and on days 1 and 7. Results In all, 18 participants met the criteria for data analysis. Compared to baseline level, only experimental group showed significant decrease of HDRS-24 score from day 3 to day 7 (P<0.05). Experimental group also showed significant improvement compared with control group from day 3 to day 7 (P<0.05). No correlation between treatment outcomes with serum BDNF levels was observed. However, experimental group showed significant correlation for serum BDNF level on day 1 with day 7 (r=0.721, P=0.028), whereas the control group did not. Conclusion Yueju likely contributes to fast-onset antidepressant effects on MDD. Further investigation is necessary to firmly establish the ancient formula as a safe, efficacious, and rapidly acting alternative medicine for MDD treatment.

Two standardized fractions of Gardenia jasminoides Ellis with rapid antidepressant effects are differentially associated with BDNF up-regulation in the hippocampus

ETHNOPHARMACOLOGICAL RELEVANCE Gardenia jasminoides Ellis (GJ) is one of the five constituents of Yueju pill, a Traditional Chinese Medicine for treatment of syndromes associated with mood disorders. Recently, preclinical and clinical studies suggest that Yueju pill confers rapid antidepressant effects. GJ is identified as the constituent primary for Yueju pills rapid antidepressant effects. GJs antidepressant action is temporally associated with up-regulated expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. The present study aimed to identify chemical fractions responsible for the rapid antidepressant efficacy of GJ and its association with BDNF signaling. MATERIALS AND METHODS Four fractions of GJ were extracted using standardized procedure. The four fractions were screened for rapid antidepressant potential, using the behavioral paradigm of forced swimming test (FST) and tail suspension test (TST) assessed at 24h post a single administration. A single dose of the putatively effective fractions was further tested in mice exposed to chronic mild stress (CMS), followed with a comprehensive behavioral testing including TST, FST, sucrose preference test (SPT), and novelty suppressed-feeding (NSF). To test the association of BDNF signaling with rapid antidepressant effects of effective factions, the expressions of BDNF and its receptor tropomyosin receptor kinase B (TrkB) in the hippocampus were assessed at different times post a single administration of effective fractions. RESULTS Both petroleum ether (GJ-PE) and n-butyl alcohol fraction (GJ-BO) fractions of GJ displayed rapid antidepressant potential in the FST. In the TST, the antidepressant effects of GJ-PE lasted for a longer time than GJ-BO. Acute administration of either GJ-PE or GJ-BO significantly reversed the behavioral deficits in the tests of TST, FST, SPT and NSF in chronically stressed mice, confirming both fractions conferred rapid antidepressant efficacy. Interestingly, GJ-PE, but not GJ-BO, increased the expression of BDNF and TrkB in the hippocampus post a single administration. CONCLUSION Two standardized fractions GJ-PE and GJ-BO exhibited comparable rapid antidepressant-like effects on the CMS mice. However, only the effects of GJ-PE was associated with BDNF signaling.

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

&NA; 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. HighlightsPPD‐F1 showed depression‐like behaviors and hippocampal Akt‐mTOR signaling deficiency at juvenile and adult stages.A single dose of ketamine reversed the behavior deficits and the impairment in Akt‐mTOR signaling in PPD‐F1.PPD‐F2 mice remained deficient in the SP and NSF test and hippocampal Akt‐mTOR signaling.

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.