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Metabolic Profiling and Phenotyping of Central Nervous System Diseases: Metabolites Bring Insights into Brain Dysfunctions

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Abstract

Metabolic phenotyping corresponds to the large-scale quantitative and qualitative analysis of the metabolome i.e., the low-molecular weight <1 KDa fraction in biological samples, and provides a key opportunity to advance neurosciences. Proton nuclear magnetic resonance and mass spectrometry are the main analytical platforms used for metabolic profiling, enabling detection and quantitation of a wide range of compounds of particular neuro-pharmacological and physiological relevance, including neurotransmitters, secondary messengers, structural lipids, as well as their precursors, intermediates and degradation products. Metabolic profiling is therefore particularly indicated for the study of central nervous system by probing metabolic and neurochemical profiles of the healthy or diseased brain, in preclinical models or in human samples. In this review, we introduce the analytical and statistical requirements for metabolic profiling. Then, we focus on key studies in the field of metabolic profiling applied to the characterization of animal models and human samples of central nervous system disorders. We highlight the potential of metabolic profiling for pharmacological and physiological evaluation, diagnosis and drug therapy monitoring of patients affected by brain disorders. Finally, we discuss the current challenges in the field, including the development of systems biology and pharmacology strategies improving our understanding of metabolic signatures and mechanisms of central nervous system diseases.

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Abbreviations

1H NMR:

Proton nuclear magnetic resonance

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

ASD:

Autism spectrum disorder

BCAA:

Branched chain amino acids

BD:

Bipolar disorder

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

DA:

Discriminant analysis

DMA:

Dimethylamine

FXS:

Fragile X Syndrome

GABA:

γ-aminobutyric acid

GC/LC:

Gas/liquid chromatography

HR:

High resolution

MAS:

Magic angle spinning

MDD:

Major depressive disorder

MS:

Mass spectrometry

NAA:

N-acetyl-aspartate

O:

Orthogonal

PCA:

Principal component analysis

PD:

Parkinson’s disease

PIP:

Phosphatidyl-inositol-phosphate

PIP2:

Phosphatidyl-inositol-diphosphate

PLS:

Partial least squares

SCA3:

Spinocerebellar ataxia 3

SCFA:

Short chain fatty acids

SCZ:

Schizophrenia

TCA:

Tricarboxylic acid

TMA:

Trimethylamine

TMAO:

Trimethylamine-N-oxide

UPLC:

Ultra performance liquid chromatography

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Acknowledgments

The authors would like to thank Mr. Frank Aguila for figure editing. LD is funded by FRAXA Research Foundation, Agence Nationale de la Recherche (ANR JCJC SVE6 MetaboXFra), Conseil Général 06, Fondation Jérôme Lejeune and the CNRS PICS program. MED and LD are funded by The Royal Society - CNRS/ International Exchange Program (IE120728) and the Coordinated Action NEURON-ERANET under European Community Framework Program grant agreement (291840) which funded the μNeuroINF project. The authors declare no conflict of interest.

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Authors and Affiliations

  1. Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK

    Marc-Emmanuel Dumas

  2. Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 7275, 660 route des Lucioles, 06 560, Valbonne, France

    Laetitia Davidovic

  3. Université de Nice-Sophia Antipolis, Nice, France

    Laetitia Davidovic

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  1. Marc-Emmanuel Dumas
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  2. Laetitia Davidovic
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Correspondence to Laetitia Davidovic.

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Dumas, ME., Davidovic, L. Metabolic Profiling and Phenotyping of Central Nervous System Diseases: Metabolites Bring Insights into Brain Dysfunctions. J Neuroimmune Pharmacol 10, 402–424 (2015). https://doi.org/10.1007/s11481-014-9578-5

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  • DOI: https://doi.org/10.1007/s11481-014-9578-5

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