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Morinda officinalis oligosaccharides (MOO) are an oral drug approved in China for the treatment of depression in China. However, MOO is hardly absorbed so that their anti-depressant mechanism has not been elucidated. Here, we show that oral MOO acted on tryptophan → 5-hydroxytryptophan (5-HTP) → serotonin (5-HT) metabolic pathway in the gut microbiota. MOO could increase tryptophan hydroxylase levels in the gut microbiota which accelerated 5-HTP production from tryptophan; meanwhile, MOO inhibited 5-hydroxytryptophan decarboxylase activity, thus reduced 5-HT generation, and accumulated 5-HTP. The raised 5-HTP from the gut microbiota was absorbed to the blood, and then passed across the blood–brain barrier to improve 5-HT levels in the brain. Additionally, pentasaccharide, as one of the main components in MOO, exerted the significant anti-depressant effect through a mechanism identical to that of MOO. This study reveals for the first time that MOO can alleviate depression via increasing 5-HTP in the gut microbiota. Up-regulating gut microbiota tryptophan hydroxylase levels and down-regulating 5-hydroxytryptophan decarboxylase activity is the molecular mechanism of action of the anti-depressant drug Morinda officinalis oligosaccharides. [Display omitted] [ABSTRACT FROM AUTHOR]

Introduction: Uwhangchungsimwon (UCW) is one of the most representative standardized herbal drugs for the treatment of central nervous system diseases, including mood disorders, and has been used for over 600 years in Korea and China. In spite of the long clinical application of UCW, no experimental evidence for its use against depressive disorders exists. Here, we performed an animal study to investigate the anti-depressive effect of UCW and the underlying mechanisms. Methods: A social isolation-induced depressive-like model was produced using C57BL/6J male mice by housing the mice individually for 31 days, and the mice underwent daily oral administration of distilled water, UCW (100, 200, 400 mg/kg) or fluoxetine (20 mg/kg) during the final 17 days. A tail suspension test (TST), forced swimming test (FST), and open field test (OFT) were used to explore the effects of UCW on depressive-like behaviors. 5-Hydroxytryptamine (5-HT) was measured in the dorsal raphe nuclei (DRN) using immunofluorescence. The serum corticosterone level was measured with its receptor and catecholamine, along with cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Results: Social isolation stress effectively induced depressive-like behaviors, and UCW treatment significantly improved the symptoms of depressive-like behavior in the FST, TST, and OFT. The isolation stress-induced depletion of 5-HT was significantly ameliorated by UCW treatment. UCW also attenuated the activation of the glucocorticoid receptor (GR) and the elevated serum corticosterone level, as well as the hippocampal levels of dopamine and norepinephrine. Dexametasone-derived translocation of GR was inhibited by UCW treatment in PC12 cells and HT22 cells. In addition, alterations of tryptophan hydroxylase 2 (TPH2), BDNF, and CREB in the protein analyses were notably regulated by UCW treatment. Conclusions: These results provide animal-based evidence for the anti-depressive effect of UCW, and its underlying mechanisms may involve regulating the serotonergic system, the hypothalamic-pituitary-adrenal (HPA) axis, and neurotrophin. [ABSTRACT FROM AUTHOR]

Background: Major depression (MD) results from a complex synergy between genetic and environmental factors. The aim of this study is to analyze the interaction of tryptophan hydroxylase 2 gene (TPH2) variation and negative life events in the pathogenesis of MD. Three TPH2 polymorphisms, -703G/T (rs4570625), -473T/A (rs11178997), and 1463G/A (rs120074175), were selected based on previous findings of associations with MD.Methods: In this study, 289 patients with MD and 289 age- and sex-matched control subjects were genotyped. The frequency and severity of negative life events were assessed by the Life Events Scale (LES). Gene-environment interactions (G×E) were assessed using the generalized multifactor dimensionality reduction (GMDR) method.Results: Differences in rs11178997 and rs120074175 allele frequencies and genotype distributions were observed between MD patients and controls. Significant G×E interactions between negative life events and allelic variation of rs4570625, rs11178997, and rs120074175 were also observed. Individuals carrying the T(-) genotype of rs4570625 (GG), T(-) genotype of rs11178997 (AA), or A(-) genotype of rs120074175 (GG) were susceptible to MD only when exposed to high-negative life events. However, individuals with the T(+) genotypes of rs11178997 (TA, TT) and A(+) genotypes of rs120074175 (AG, AA) were susceptible to MD when exposed to low-negative life events.Limitation: Assessment of negative life events was influenced by subjective interpretation.Conclusions: Interactions between multiple TPH2 gene alleles and negative life events were revealed by GMDR analysis. Chinese Han individuals with at least one rs11178997 T allele or rs120074175 A allele are susceptible to MD even in the relative absence of high-negative life events. [ABSTRACT FROM AUTHOR]

Human TPH2 ( hTPH2) catalyzes the rate-limiting step in CNS serotonin biosynthesis. We characterized a single-nucleotide polymorphism (C2755A) in the hTPH2 gene that substitutes tyrosine for serine at position 41 in the regulatory domain of the enzyme. This polymorphism is associated with bipolar disorder and peripartum depression in a Chinese population. Recombinant h TPH2 human proteins were expressed in bacteria and also stably expressed in PC12 cells. Following bacterial expression and purification, the tyrosine for serine substitution at position 41 (S41Y) polymorphic enzyme displayed increased Vmax with unchanged Km values. By contrast, enzyme stability was decreased in vitro from 32 min to 4 min (37°C) for the S41Y enzyme (as compared to the wild-type enzyme). The S41Y polymorphism decreased cyclic AMP-dependent protein kinase A-mediated phosphorylation ~ 50% relative to wild-type hTPH2, suggesting that the S41Y mutation may disrupt the post-translational regulation of this enzyme. Transfected PC12 cells expressed hTPH2 mRNA, active protein, and synthesized and released serotonin. Paradoxically, while S41Y-transfected PC12 cells expressed higher levels of hTPH2 than wild type, they synthesized less serotonin. These findings suggest a modified regulation of the S41Y gene variant leading to altered regulation and reduced neurotransmitter synthesis that may contribute to association of the polymorphism with bipolar disorder and depression. [ABSTRACT FROM AUTHOR]

Background: Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme in the synthetic pathway for brain serotonin and is considered key factor for maintaining normal serotonin transmission in the central neuron system (CNS). Gene-disease association studies have reported a relationship between TPH2 and major depressive disorder (MDD) in different populations, however subsequent studies have produced contradictory results. Objectives: We performed a systematic overview and a meta-analysis with all available data up-to-date. Methods: We scrutinized PubMed, Embase, HuGNet and China National Knowledge Infrastructure (CNKI ) and last update was held on October 2011. We also searched the manuscripts and the supplementary documents of the published genomewide association studies in the field. Effect sizes of independent loci that have been studied in more than 3 articles were synthesized using fixed and random effects models. Results: We found 27 eligible articles that studied a total of 74 single nucleotide polymorphisms (SNPs). Finally, 12 independent loci were included in the meta-analysis. The synthesis of the data shown that two SNPs (rs4570625 and rs17110747) were associated with MDD using fixed effects models. SNP rs4570625 had low heterogeneity and remained significant using the more conservative random effects calculations with a summary OR = 0.83 (95% CI: 0.73-0.96). Conclusion: The current study identified a SNP (rs4570625) with strong epidemiological credibility; however more studies are required to provide robust evidence for other weak associations. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between the tryptophan hydroxylase-2 (TPH2) gene (G1463A) polymorphism and unipolar depression in a southern Chinese Han population. Participants and Methods: The allelic and genotypic frequencies of TPH2 gene G1463A polymorphism were examined with the amplification refractory mutation system-polymerase chain reaction technique in 123 unipolar depressive patients and 122 healthy individuals. Patients and healthy controls were all from the Guangdong Han population in southern China. Results: No subjects among the cases or controls were found to carry any TPH2 1463A allele. Conclusion: There is no association identified between the TPH2 G1463A polymorphism and unipolar depression in the southern Chinese Han population. [ABSTRACT FROM AUTHOR]