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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

Brain and serum serotonin concentrations of the a) pCPA-treated mice (n = 10) and b) Tph2-/- mice (n = 10).Data are expressed as mean values ± standard deviation.
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f1: Brain and serum serotonin concentrations of the a) pCPA-treated mice (n = 10) and b) Tph2-/- mice (n = 10).Data are expressed as mean values ± standard deviation.

Mentions: Mice were treated with 500 mg/kg pCPA or saline for three consecutive days. Serotonin levels were significantly reduced in both the brains and sera of the pCPA-treated mice compared with control mice (Fig. 1a). Non-targeted metabolomics approach using ultra-performance liquid chromatography - quadrupole time-of-flight mass spectrometry (UPLC-QTof-MS) was employed to identify potential biomarkers perturbed by the pharmacologically induced serotonin deficiency in the pCPA-treated mice. Principal component analysis (PCA) was performed to highlight key differences between the pCPA-treated and control mice (Fig. 2a,c). Orthogonal partial least squares discriminant analysis (OPLS-DA) further demonstrated a clear metabolic differentiation between the two sample groups (Fig. 2b,d). Variable importance for projection (VIP) scores were obtained for each metabolite based on its individual contribution to the statistical discrimination. In total, 33 preliminary metabolites were found to meet the selection criteria (VIP > 2.0, p-value < 0.05, fold change > 1.5) and selected for further characterization.


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)

Brain and serum serotonin concentrations of the a) pCPA-treated mice (n = 10) and b) Tph2-/- mice (n = 10).Data are expressed as mean values ± standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Brain and serum serotonin concentrations of the a) pCPA-treated mice (n = 10) and b) Tph2-/- mice (n = 10).Data are expressed as mean values ± standard deviation.
Mentions: Mice were treated with 500 mg/kg pCPA or saline for three consecutive days. Serotonin levels were significantly reduced in both the brains and sera of the pCPA-treated mice compared with control mice (Fig. 1a). Non-targeted metabolomics approach using ultra-performance liquid chromatography - quadrupole time-of-flight mass spectrometry (UPLC-QTof-MS) was employed to identify potential biomarkers perturbed by the pharmacologically induced serotonin deficiency in the pCPA-treated mice. Principal component analysis (PCA) was performed to highlight key differences between the pCPA-treated and control mice (Fig. 2a,c). Orthogonal partial least squares discriminant analysis (OPLS-DA) further demonstrated a clear metabolic differentiation between the two sample groups (Fig. 2b,d). Variable importance for projection (VIP) scores were obtained for each metabolite based on its individual contribution to the statistical discrimination. In total, 33 preliminary metabolites were found to meet the selection criteria (VIP > 2.0, p-value < 0.05, fold change > 1.5) and selected for further characterization.

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