Antidepressant-Like Effects and Cognitive Enhancement of Coadministration of Chaihu Shugan San and Fluoxetine: Dependent on the BDNF-ERK-CREB Signaling Pathway in the Hippocampus and Frontal Cortex.
ABSTRACT: Background:Fluoxetine (FLU) is the first-line and widely used medication for depression; however, FLU treatment is almost ineffective in 30%-40% of patients with depression. In addition, there are some problems in FLU treatment, such as delayed efficacy, large side effects, and poor tolerance. Chaihu Shugan San (CSS) is a classic and effective antidepressant Chinese herbal medicine that has been used in China for thousands of years. CSS or coadministration of CSS and FLU has become one of the most recommended methods in the treatment of depression in China. However, the specific pathways of CSS and coadministration of CSS and FLU for antidepressant are still unclear. Objective:This study was designed to evaluate the antidepressant effects of CSS and coadministration of CSS and FLU. Methods:The chronic unpredictable mild stress (CUMS) rat model was used to simulate depression. 120 healthy adult male Sprague-Dawley (SD) rats were randomly divided into seven groups: the control group, CUMS group, low-dose CSS group, high-dose CSS group, FLU group, coadministration of low-dose CSS and FLU group, and coadministration of high-dose CSS and FLU group. The rats in different groups were given different interventions. Then, the depression-like behavior and cognitive function were evaluated by the sucrose preference test (SPT), forced swimming test (FST), open field test (OFT), and Y-maze test. What is more, the antidepressant mechanism of CSS and coadministration of CSS and FLU were studied through BDNF mRNA, ERK mRNA, CREB mRNA, BDNF, p-ERK/ERK, and p-CREB/CREB levels in the hippocampus and frontal cortex by Western blot and RT-PCR. Results:Compared with the CUMS group, CSS and coadministration of CSS and FLU could alleviate the depressive symptoms and improve cognitive function in CUMS rats (p < 0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (p < 0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (p < 0.05); CSS and coadministration of CSS and FLU could increase the expression of BDNF, p-CREB/CREB, p-ERK/ERK, and BDNF mRNA, CREB mRNA, and ERK mRNA in the hippocampus and frontal cortex (Discussion and Conclusion. Finally, we found that both CSS and coadministration of CSS and FLU play an antidepressant role, which may be due to the regulation of the BDNF/ERK/CREB signaling pathway in the hippocampus and frontal cortex. Among them, the coadministration of CSS and FLU can enhance the antidepressant effect of CSS or FLU alone, and the underlying mechanism needs further investigation.
Project description:Neuronal damage is related to the onset and treatment of depressive disorders. Antidepressant-like effects have been elicited by paeoniflorin on animal models. The aim of this study is to demonstrate whether the neuroprotective effect of paeoniflorin on rats suffered from chronic unpredictable mild stress (CUMS) was regulated by the ERK-CREB signaling pathway. Results showed that paeoniflorin not only ameliorated depressive-like behavior with low locomotor activity and prolonged immobility duration in our forced swimming test but also reduced sucrose consumption. Paeoniflorin treatment decreased the degree of neuronal damage in the hippocampus of the model rats. Conversely, it markedly increased the mRNA levels of ERK1, ERK2, and CREB and the levels of ERK, p-ERK, CREB, and p-CREB protein expression in the hippocampus. Blockade of the ERK-CREB axis with the ERK-specific inhibitor U0126 repressed the neuroprotective and antidepressant-like effects of paeoniflorin on rats in the setting of chronic-mild-stress and abolished the recoveries of p-ERK mediated by paeoniflorin treatment. Thus, paeoniflorin possibly exerted a neuroprotective effect modulated by the ERK-CREB signaling pathway on CUMS-induced hippocampal damage in rats.
Project description:<b>Objectives:</b> To evaluate the pharmacodynamical effects and pharmacological mechanism of Ginsenoside H dripping pills (GH) in chronic unpredictable mild stress (CUMS) model rats. <b>Methods:</b> First, the CUMS-induced rat model was established to assess the anti-depressant effects of GH (28, 56, and 112 mg/kg) by the changes of the behavioral indexes (sucrose preference, crossing score, rearing score) and biochemical indexes (serotonin, dopamine, norepinephrine) in Hippocampus. Then, the components of GH were identified by ultra-performance liquid chromatography-iron trap-time of flight-mass spectrometry (UPLC/IT-TOF MS). After network pharmacology analysis, the active ingredients of GH were further screened out based on OB and DL, and the PPI network of putative targets of active ingredients of GH and depression candidate targets was established based on STRING database. The PPI network was analyzed topologically to obtain key targets, so as to predict the potential pharmacological mechanism of GH acting on depression. Finally, some major target proteins involved in the predictive signaling pathway were validated experimentally. <b>Results:</b> The establishment of CUMS depression model was successful and GH has antidepressant effects, and the middle dose of GH (56 mg/kg) showed the best inhibitory effects on rats with depressant-like behavior induced by CUMS. Twenty-eight chemical components of GH were identified by UPLC/IT-TOF MS. Subsequently, 20(<i>S</i>)-ginsenoside Rh2 was selected as active ingredient and the PPI network of the 43 putative targets of 20(<i>S</i>)-ginsenoside Rh2 containing in GH and the 230 depression candidate targets, was established based on STRING database, and 47 major targets were extracted. Further network pharmacological analysis indicated that the cAMP signaling pathway may be potential pharmacological mechanism regulated by GH acting on depression. Among the cAMP signaling pathway, the major target proteins, namely, cAMP, PKA, CREB, <i>p</i>-CREB, BDNF, were used to verify in the CUMS model rats. The results showed that GH could activate the cAMP-PKA-CREB-BDNF signaling pathway to exert antidepressant effects. <b>Conclusions:</b> An integrative pharmacology-based pattern was used to uncover that GH could increase the contents of DA, NE and 5-HT, activate cAMP-PKA-CREB-BDNF signaling pathway exert antidepressant effects.
Project description:Antidepressant medications are known to modulate the central nervous system, and gut microbiota can play a role in depression via microbiota-gut-brain axis. But the impact of antidepressants on gut microbiota function and composition remains poorly understood. Thus this study assessed the effect of serotonin reuptake inhibitor antidepressant fluoxetine (Flu) and tricyclic antidepressant amitriptyline (Ami) administration on gut microbiota composition, diversity, and species abundance, along with microbial function in a chronic unpredictable mild stress (CUMS)-induced depression rat model. Oral administration of Ami and Flu significantly altered the overall gut microbiota profile of CUMS-induced rats, as assessed using the permutational multivariate analysis of variance test. At the phylum level, 6-week of antidepressant treatment led to a decreased Firmicutes/Bacteroidetes ratio due to an enhanced Bacteroidetes and reduced Firmicutes relative abundance. Flu was more potent than Ami at altering the Firmicutes and Bacteroidetes levels in the CUMS rats. At the family level, both antidepressants significantly increased the abundance of Porphyromonadaceae. However, an increased Bacteroidaceae level was significantly associated with Ami, not Flu treatment. Furthermore, at the genus level, an increase in the relative abundance of Parabacteroides, Butyricimonas, and Alistipes was observed following Ami and Flu treatment. Subsequent metagenomics and bioinformatics analysis further indicated that Ami and Flu likely also modulated metabolic pathways, such as those involved in carbohydrate metabolism, membrane transport, and signal transduction. Additionally, both antidepressants affected antibiotic resistome, such as for aminoglycoside (aph3iiiA), multidrug (mdtK, mdtP, mdtH, mdtG, acrA), and tetracycline (tetM) resistance in CUMS rats. These data clearly illustrated the direct impact of oral administration of Flu and Ami on the gut microbiome, thus set up the foundation to reveal more insights on the therapeutic function of the antidepressants and their overall contribution to host health.
Project description:Panax ginseng C.A. Meyer (Araliaceae), a popular tonic and dietetic herbal medicine, has been traditionally prescribed in China and other countries to treat affective disorders. The medicinal parts of ginseng, the roots and flower buds, have become increasingly popular as dietary supplements due to the current holistic healthcare trend. We have investigated for the first time the antidepressive actions of the different medicinal parts, namely, the main roots, fibrous roots, and flower buds (in water extract and powder), of garden-cultivated ginseng through behavioral and drug-induced tests in mice. The water extracts, but not the powders of ginseng fibrous roots, flower buds, and main roots (1.5 g of crude drug per kilogram, p.o.), significantly reduced the immobility time in the forced swim test (FST) and tail suspension test (TST); moreover, the water extracts enhanced the 5-hydroxytryptophan (5-HTP)-induced head-twitch response and antagonized the action of reserpine in the mouse. We then explored the antidepressive mechanism of action of the ginsenoside Rb1 (Rb1) related to the brain-derived neurotrophic factor (BDNF) and its downstream proteins in mice exposed to chronic unpredictable mild stress (CUMS). Treatment with Rb1 (20 mg/kg, p.o.) for 21 days significantly attenuated the CUMS-induced decrease in the activities of BDNF, tropomyosin-related kinase B (TrkB), protein kinase B (AKT), extracellular regulatory protein kinase (ERK), and cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) in the mouse hippocampal CA3 region and prefrontal cortex (PFC). Interestingly, treatment with the novel TrkB antagonist ANA-12 (0.5 mg/kg, i.p.) did not alter the level of BDNF but significantly blocked the antidepressive effects of Rb1 on proteins downstream of BDNF in CUMS-treated mice. These results suggest that BDNF-TrkB-CREB signaling may be involved in the antidepressive mechanism of the action of Rb1.
Project description:The present study hypothesized that caffeic acid (3,4?dihydroxycinnamic acid; CaA) may exert antidepressant?like effects in rats with chronic unpredictable mild stress via epigenetic mechanisms, such as DNA methylation and hydroxymethylation. The chronic unpredictable mild stress (CUMS) model was used to analyze the effects of CaA on behavioral phenotypes, and to evaluate the distribution of 5?methylcytosine (5mC) and 5?hydroxymethylcytosine (5hmC) in the hippocampus and prefrontal cortex using immunohistochemistry and immunofluorescence. mRNA levels of the genes encoding brain?derived neurotropic factor (BDNF) and catechol?O?methyltransferase (COMT), and key enzymes regulating DNA methylation [DNA methyltransferase (DNMT)1 and DNMT3A] and hydroxymethylation [Ten?eleven translocation (TET)1?3] were examined using quantitative (q)PCR. Furthermore, enrichment of 5mC and 5hmC at the promotor regions of the Bdnf and Comt genes was quantified using chromatin immunoprecipitation?qPCR. Behavioral data showed that CaA exerted a slight antidepressant?like effect. Bdnf and Comt genes showed differential expression patterns due to CUMS. CaA intervention induced different Dnmt1/Dnmt3a and Tet1/Tet2 mRNA levels in the hippocampus and prefrontal cortex, respectively. CaA regulated the ratio of 5mC/5hmC at the promotor region of the Bdnf and Comt genes and therefore influenced gene expression, which may be a valuable therapeutic option for major depressive disorder (MDD). In conclusion, there were epigenetic changes in the hippocampus and prefrontal cortex in CUMS rats, and CaA may function as a modulator of DNA methylation to regulate gene transcription, thus providing a mechanistic basis for the use of this phytochemical agent in the treatment of MDD.
Project description:(5S,10R)-5-methyl-10,11-dihydro-5H-dibenzo(A,D)cyclohepten-5,10-imine hydrogen maleate (MK-801) is an N-methyl-D-aspartate non-competitive antagonist that possesses useful biological properties, including anticonvulsant and anesthetic activities. Studies have indicated the rapid antidepressant effects of MK-801 in animal models. However, there are no reports concerning a sustained antidepressant effect in the chronic unpredictable mild stress (CUMS) model. Furthermore, the antidepressant mechanism remains unclear. The aim of the present study was to examine the effects of MK-801 (0.1 mg/kg) and rapastinel (10 mg/kg) on depression-like behavior in CUMS mice and measure the protein expression of brain-derived neurotrophic factor (BDNF), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (GluA1) and phosphorylated mammalian target of rapamycin (p-mTOR). In the tail suspension and forced swim tests, MK-801 significantly attenuated the increased immobility time in CUMS mice compared with the vehicle group. In the sucrose preference test, a single-dose injection of MK-801 significantly ameliorated the decreased sucrose preference in CUMS mice compared with the vehicle group. Western blot analyses indicated that MK-801 significantly attenuated the decreased BDNF, GluA1 and p-mTOR protein levels in the medial prefrontal cortex (mPFC), dentate gyrus (DG) and CA3 of the hippocampi of CUMS mice. Conversely, this compound had no effect on increased BDNF, GluA1 and p-mTOR protein levels in the nucleus accumbens of CUMS mice. Therefore, the present study revealed the sustained antidepressant effects of MK-801 in the CUMS model. Furthermore, synaptogenesis and neuronal regeneration in the prelimbic regions of mPFC, DG and CA3 of the hippocampus may be implicated as mechanisms that promote a sustained antidepressant response.
Project description:BACKGROUND:Depression is a serious and common psychiatric disorder generally affecting more women than men. A woman's risk of developing depression increases steadily with age, and higher incidence is associated with the onset of menopause. Here we evaluated the antidepressant properties of Asparagus cochinchinensis (AC) extract and investigated its underlying mechanisms in a rat menopausal depression model. METHODS:To model this menopausal depression, we induced a menopause-like state in rats via ovariectomy and exposed them to chronic unpredictable mild stress (CUMS) for 6?weeks, which promotes the development of depression-like symptoms. During the final 4?weeks of CUMS, rats were treated with either AC extract (1000 or 2000?mg/kg, PO), which has been reported to provide antidepressant effects, or with the tricyclic antidepressant imipramine (10?mg/kg, IP). RESULTS:We report that CUMS promotes depression-like behavior and significantly increases serum corticosterone and inflammatory cytokine levels in the serum of ovariectomized (OVX) rats. We also found that CUMS decreases the expression of brain-derived neurotrophic factor (BDNF) and its primary receptor, tropomyosin receptor kinase B (TrkB), in OVX rats, and treatment with AC extract rescues both BDNF and TrkB expression levels. CONCLUSION:These results suggest that AC extract exerts antidepressant effects, possibly via modulation of the BDNF-TrkB pathway, in a rat model of menopausal depression.
Project description:BACKGROUND:Depression is characterized by significant and low mood. Classical antidepressants are still not adequate in treating depression because of undesirable side effects. Folic acid, a member of the vitamin B complex, in considered to be strongly associated with the function and development of the central nervous system. Thus, in this study, we established a model of depression through chronic unpredictable mild stress (CUMS) in rats and assessed the antidepressant effects and mechanisms of folic acid. METHODS:Sprague-Dawley rats were randomly divided into four groups: control, chronic unpredictable mild stress (CUMS), CUMS treated with folic acid, and CUMS treated with citalopram. Rats were assessed in terms of weight change, open-field test and sucrose preference. Homocysteine, monoamine neurotransmitters, interleukin-6, brain-derived neurotrophic factor (BDNF), ?-endorphin levels in the serum and brains of rats were analysed. RESULTS:Folic acid exhibited antidepressant-like effects in open-field and sucrose preference tests. Folic acid treatment effectively increased the levels of monoamine neurotransmitters, BDNF and ?-endorphin, interleukin-6 and homocysteine levels were also significantly suppressed by folic acid administration. CONCLUSIONS:These findings serve as preclinical evidence that folic acid plays an antidepressant-like role in several pathways involving monoamine neurotransmitters. Thus, folic acid may be used as a potential antidepressant.
Project description:Although ketamine shows a rapid and sustained antidepressant effect, the precise mechanisms underlying its effect are unknown. Recent studies indicate a key role of p11 (also known as S100A10) in depression-like behavior in rodents. The present study aimed to investigate the role of p11 in the antidepressant-like action of ketamine in chronic unpredictable mild stress (CUMS) rat model. The open-field test, forced swimming test and sucrose preference test were performed after administration of ketamine (10 mg kg(-1)) or a combination of ketamine and ANA-12 (a tropomyosin-related kinase B (TrkB) antagonist; 0.5 mg kg(-1)). The lentivirus vector for p11 was constructed to knock down the hippocampal expression of p11. In the CUMS rats, ketamine showed a rapid (0.5 h) and sustained (72 h) antidepressant effect, and its effect was significantly blocked by co-administration of ANA-12. Furthermore, ketamine significantly increased the reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of CUMS rats, whereas ketamine did not affect the expression of p11 in CUMS rats 0.5 h after administration. In addition, ketamine significantly increased the reduced ratio of p-TrkB/TrkB in the hippocampus by CUMS rats, and its effect was also blocked by ANA-12. Moreover, the reduced expression of BDNF and p11 in the hippocampus of CUMS rats was significantly recovered to control levels 72 h after ketamine administration. Interestingly, knockdown of hippocampal p11 caused increased immobility time and decreased sucrose preference, which were not improved by ketamine administration. These results suggest that p11 in the hippocampus may have a key role in the sustained antidepressant effect of ketamine in the CUMS model of depression.
Project description:This study was designed to investigate the effect of the cortical cyclooxygenase-2 (COX2) pathway on depressive behaviour in rats. Meloxicam, COX2 overexpressed lentivirus and COX2 RNAi lentivirus were administered to Sprague-Dawley rats subjected to chronic unpredictable mild stress (CUMS). Behaviour tests, biochemistry and immunohistochemistry methods, enzyme-linked immunosorbent assays, western blotting and reverse transcription polymerase chain reactions were used to evaluate the changes in rat behaviour and the cortical COX2 pathway. CUMS rats showed depressive-like behaviours. The superoxide dismutase activity and cyclic adenosine monophosphate (cAMP) contents were significantly decreased, the contents of malondialdehyde, prostaglandin E2 (PGE2) and inflammatory cytokines were significantly increased. The expressions of protein kinase A (PKA) and cAMP response element-binding protein (CREB) were decreased, and the levels of brain-derived neurotrophic factor (BDNF) and COX2 were significantly increased. Meloxicam and COX2 RNAi lentivirus significantly alleviated the abnormalities induced by CUMS, while COX2 overexpressed lentivirus aggravated these abnormalities. Our results indicated that the cortical COX2 pathway was activated in CUMS rats. Inhibition of COX2 activity/expression can obviously improve depressive behaviours in CUMS rats. Upregulating COX2 expression can increase the susceptibility of rats to CUMS. An imbalance in the cortical COX2-PGE2-cAMP/PKA-CREB-BDNF signalling pathway participates in the pathogenic mechanism of depression.