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Background Phosphodiesterase 4 is a promising target for developing novel antidepressants. However, prototype phosphodiesterase 4 inhibitors show severe side effects, including nausea and vomiting. N-Isopropyl-3-(cyclopropylmethoxy)-4-difluoromethoxy benzamide (FCPR03) is a novel phosphodiesterase 4 inhibitor with little emetic potential. In the present study, we investigated the inhibitory effect of FCPR03 on chronic unpredictable mild stress-induced, depressive-like behaviors in mice and explored the underlying mechanisms. Methods The depression model of mice was established by chronic unpredictable mild stress. Forced swim test, tail suspension test, and sucrose preference test were used to assess depressive-like behaviors. Golgi-staining was utilized to analyze dendritic morphology and spine density. The level of cAMP was measured by enzyme-linked immnosorbent assay assay. Western blot was used to evaluate protein levels of phosphorylated cAMP-response element binding protein, protein kinase B, glycogen synthase kinase-3β, and brain derived neurotrophic factor in both hippocampus and prefrontal cortex. Postsynaptic density protein 95 and synapsin 1 were also detected by western blot in the hippocampi. Results Treatment with FCPR03 (0.5–1.0 mg/kg, i.p.) increased consumption of sucrose in the sucrose preference test in mice exposed to chronic unpredictable mild stress. FCPR03 shortened the immobility time in forced swim test and tail suspension test without affecting locomotor activity. Furthermore, chronic unpredictable mild stress decreased the dendritic spine density and dendritic length in the hippocampus. This change was accompanied by decreased expression of postsynaptic density protein 95 and synapsin 1. Interestingly, FCPR03 prevented dendritic spine loss and increased synaptic protein levels. Moreover, the levels of cAMP, phosphorylated cAMP-response element binding protein, and brain derived neurotrophic factor were elevated in chronic unpredictable mild stress-challenged mice after treatment with FCPR03. In addition, FCPR03 also enhanced the phosphorylation of both protein kinase B and glycogen synthase kinase-3β in mice exposed to chronic unpredictable mild stress. Conclusion The present study suggests that FCPR03 could prevent both depressive-like behaviors and spine loss induced by chronic unpredictable mild stress in the mice hippocampi. [ABSTRACT FROM AUTHOR]

Cinnamomi Cortex (CC, rougui) is the stripped trunk bark of Cinnamomum cassia Presl (CCP) and commonly is used to treat dyspepsia, gastritis, blood circulation disturbances, and inflammatory diseases. However, Cinnamomum burmannii Blume (CBB), an edible ingredient in food from a different Cinnamomum, sometimes replaces CC due to their similar functions and appearance. To identify and distinguish CC from CBB, we investigated the metabolite differences in polar and non-polar extracts of these species by high-resolution H nuclear magnetic resonance (H NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) combined with multivariate statistical analyses. The results showed a significantly higher separation in GC-MS analysis (non-polar extracts) than H NMR analysis (polar extracts). One-way ANOVA revealed that polar extracts (acetate, α-glucose, sucrose, glycerol, fructose) and non-polar extracts ( trans-cinnamaldehyde, α-copaene, δ-cadinene, 2-methoxycinnamaldehyde, (−)-calamenene, α-muurolene, γ-muurolene, α-calacorene, cubenol and α-muurolol) contributed greatly to the comparison of CC and CBB. These results indicate that the H NMR- and GC-MS-based metabolomic approach can effectively differentiate the phytochemical compositions among different species in plants, which in turn could identify important metabolites with known pharmacological activity. [ABSTRACT FROM AUTHOR]

Background: Coptidis Rhizome (CR), widely applied to treat with heat and toxicity, is one of the most commonly used traditional Chinese medicine (TCM), however, an extensive dosage can induce toxicity. Diarrhea is one of the most frequent side effects of CR treatment. Methodology/Principal Findings: In this study, metabonomics was combined with the multivariate statistical analysis to discover the endogenous metabolites which related to the diarrheal induced by CR. The male Sprague–Dawley rats were dosed with 4.95 g CR/kg weight. Urine samples were collected at day −1 (before treatment), and days 14 and 21 for NMR analysis. Serum and tissues were collected at day 14 for GC-MS analysis and histopathological examination, respectively. The urine and serum metabolic profiles provided clearer distinction between CR-treated group and control group, which was confirmed by body weight change and diarrhea. Through multivariate statistical analysis, 12 marker metabolites from 1H NMR and 8 ones from GC-MS have been found. Among those metabolites, hippurate, acetate, alanine, glycine and glutamate are likely to break the balance of gut microbiota, whereas, lactate and 2-ketoisovalerate showed association with energy metabolism. Meanwhile, we observed that the CR-induced toxicity will recover when the treatment was stopped. Conclusions/significance: These results suggest that the main reason for the CR-associated diarrhea might be disturbance in the normal gut microbiota. This metabonomics approach may provide an effective way to study the alteration of gut microbiota, which is expected to find broader application in other drug-induced gastrointestinal reaction assessment. [ABSTRACT FROM AUTHOR]

Background: Coptidis Rhizome (CR), widely applied to treat with heat and toxicity, is one of the most commonly used traditional Chinese medicine (TCM), however, an extensive dosage can induce toxicity. Diarrhea is one of the most frequent side effects of CR treatment., Methodology/principal Findings: In this study, metabonomics was combined with the multivariate statistical analysis to discover the endogenous metabolites which related to the diarrheal induced by CR. The male Sprague-Dawley rats were dosed with 4.95 g CR/kg weight. Urine samples were collected at day -1 (before treatment), and days 14 and 21 for NMR analysis. Serum and tissues were collected at day 14 for GC-MS analysis and histopathological examination, respectively. The urine and serum metabolic profiles provided clearer distinction between CR-treated group and control group, which was confirmed by body weight change and diarrhea. Through multivariate statistical analysis, 12 marker metabolites from ¹H NMR and 8 ones from GC-MS have been found. Among those metabolites, hippurate, acetate, alanine, glycine and glutamate are likely to break the balance of gut microbiota, whereas, lactate and 2-ketoisovalerate showed association with energy metabolism. Meanwhile, we observed that the CR-induced toxicity will recover when the treatment was stopped., Conclusions/significance: These results suggest that the main reason for the CR-associated diarrhea might be disturbance in the normal gut microbiota. This metabonomics approach may provide an effective way to study the alteration of gut microbiota, which is expected to find broader application in other drug-induced gastrointestinal reaction assessment.