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Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency.

Weng R, Shen S, Tian Y, Burton C, Xu X, Liu Y, Chang C, Bai Y, Liu H - Sci Rep (2015)

Bottom Line: This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-).These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms.These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.

View Article: PubMed Central - PubMed

Affiliation: Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Institute of Analytical Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

ABSTRACT
Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer's disease and Parkinson's disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.

No MeSH data available.


Related in: MedlinePlus

Heat map denoting fold changes (over normalized means) of the 21 biomarkers in mice injected with increasing dosages of pCPA and the control mice (n = 10).Columns correspond to different mice groups, and rows correspond to the altered metabolites. Shades of red represent elevated levels of metabolite, and shades of green represent reduced levels of the metabolites.
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f3: Heat map denoting fold changes (over normalized means) of the 21 biomarkers in mice injected with increasing dosages of pCPA and the control mice (n = 10).Columns correspond to different mice groups, and rows correspond to the altered metabolites. Shades of red represent elevated levels of metabolite, and shades of green represent reduced levels of the metabolites.

Mentions: A pCPA dose-response study was conducted to confirm the relationships between the 33 preliminary identified metabolites and the pCPA-induced serotonin deficiency. Four groups of mice were treated with variable pCPA doses and the resulting candidate biomarker levels were semi-quantitatively compared. The 33 candidate biomarkers were analyzed using a triple quadrupole mass spectrometer (QQQ-MS) operating under multiple reaction monitoring (MRM) mode. Twenty-one of these candidates were found to be affected by the pCPA treatment dose (Supplementary Figure S1). The 21 biomarkers were therefore considered to be directly correlated with serotonin deficiency and selected as the reliable biomarkers of serotonin deficiency. Specifically, up-regulated metabolites included kynurenine, kynurenate, 3-hydroxykynurenine, phenylalanine, hippurate, guanosine, hypoxanthine and lysoPCs, while down-regulated metabolites included serotonin, 5-hydroxyindoleacetate, tyrosine, xanthine, uric acid, citrate, oxoglutarate, succinate, creatinine, 3-indolepropionic acid and indoxyl sulfate (Fig. 3). Statistics for each compound have been summarized in Table 1.


Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency.

Weng R, Shen S, Tian Y, Burton C, Xu X, Liu Y, Chang C, Bai Y, Liu H - Sci Rep (2015)

Heat map denoting fold changes (over normalized means) of the 21 biomarkers in mice injected with increasing dosages of pCPA and the control mice (n = 10).Columns correspond to different mice groups, and rows correspond to the altered metabolites. Shades of red represent elevated levels of metabolite, and shades of green represent reduced levels of the metabolites.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495385&req=5

f3: Heat map denoting fold changes (over normalized means) of the 21 biomarkers in mice injected with increasing dosages of pCPA and the control mice (n = 10).Columns correspond to different mice groups, and rows correspond to the altered metabolites. Shades of red represent elevated levels of metabolite, and shades of green represent reduced levels of the metabolites.
Mentions: A pCPA dose-response study was conducted to confirm the relationships between the 33 preliminary identified metabolites and the pCPA-induced serotonin deficiency. Four groups of mice were treated with variable pCPA doses and the resulting candidate biomarker levels were semi-quantitatively compared. The 33 candidate biomarkers were analyzed using a triple quadrupole mass spectrometer (QQQ-MS) operating under multiple reaction monitoring (MRM) mode. Twenty-one of these candidates were found to be affected by the pCPA treatment dose (Supplementary Figure S1). The 21 biomarkers were therefore considered to be directly correlated with serotonin deficiency and selected as the reliable biomarkers of serotonin deficiency. Specifically, up-regulated metabolites included kynurenine, kynurenate, 3-hydroxykynurenine, phenylalanine, hippurate, guanosine, hypoxanthine and lysoPCs, while down-regulated metabolites included serotonin, 5-hydroxyindoleacetate, tyrosine, xanthine, uric acid, citrate, oxoglutarate, succinate, creatinine, 3-indolepropionic acid and indoxyl sulfate (Fig. 3). Statistics for each compound have been summarized in Table 1.

Bottom Line: This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-).These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms.These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.

View Article: PubMed Central - PubMed

Affiliation: Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Institute of Analytical Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

ABSTRACT
Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer's disease and Parkinson's disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.

No MeSH data available.


Related in: MedlinePlus