TY - JOUR
T1 - Untargeted plasma metabolomics identifies endogenous metabolite with drug-like properties in chronic animal model of multiple sclerosis
AU - Poisson, Laila M.
AU - Suhail, Hamid
AU - Singh, Jaspreet
AU - Datta, Indrani
AU - Deni, Aleksandar
AU - Labuzek, Krzysztof
AU - Hoda, Nasrul
AU - Shankar, Ashray
AU - Kumar, Ashok
AU - Cerghet, Mirela
AU - Elias, Stanton
AU - Mohney, Robert P.
AU - Rodriguez, Moses
AU - Rattan, Ramandeep
AU - Mangalam, Ashutosh K.
AU - Giri, Shailendra
N1 - Publisher Copyright:
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2015/12/25
Y1 - 2015/12/25
N2 - We performed untargeted metabolomics in plasma of B6 mice with experimental autoimmune encephalitis (EAE) at the chronic phase of the disease in search of an altered metabolic pathway(s). Of 324 metabolites measured, 100 metabolites that mapped to various pathways (mainly lipids) linked to mitochondrial function, inflammation, and membrane stability were observed to be significantly altered between EAE and control (p > 0.05, false discovery rate >0.10). Bioinformatics analysis revealed six metabolic pathways being impacted and altered in EAE, including <-linolenic acid and linoleic acid metabolism (PUFA). The metabolites of PUFAs, includingω-3 andω-6 fatty acids, are commonly decreased in mouse models of multiple sclerosis (MS) and in patients with MS. Daily oral administration of resolvin D1, a downstream metabolite ofω-3, decreased disease progression by suppressing autoreactive T cells and inducing an M2 phenotype of monocytes/macrophages and resident brain microglial cells. This study provides a proof of principle for the application of metabolomics to identify an endogenous metabolite(s) possessing drug-like properties, which is assessed for therapy in preclinical mouse models of MS.
AB - We performed untargeted metabolomics in plasma of B6 mice with experimental autoimmune encephalitis (EAE) at the chronic phase of the disease in search of an altered metabolic pathway(s). Of 324 metabolites measured, 100 metabolites that mapped to various pathways (mainly lipids) linked to mitochondrial function, inflammation, and membrane stability were observed to be significantly altered between EAE and control (p > 0.05, false discovery rate >0.10). Bioinformatics analysis revealed six metabolic pathways being impacted and altered in EAE, including <-linolenic acid and linoleic acid metabolism (PUFA). The metabolites of PUFAs, includingω-3 andω-6 fatty acids, are commonly decreased in mouse models of multiple sclerosis (MS) and in patients with MS. Daily oral administration of resolvin D1, a downstream metabolite ofω-3, decreased disease progression by suppressing autoreactive T cells and inducing an M2 phenotype of monocytes/macrophages and resident brain microglial cells. This study provides a proof of principle for the application of metabolomics to identify an endogenous metabolite(s) possessing drug-like properties, which is assessed for therapy in preclinical mouse models of MS.
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U2 - 10.1074/jbc.M115.679068
DO - 10.1074/jbc.M115.679068
M3 - Article
C2 - 26546682
AN - SCOPUS:84951763648
SN - 0021-9258
VL - 290
SP - 30697
EP - 30712
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 52
ER -