title: Untargeted Plasma Metabolomics Identifies Endogenous Metabolite with Drug-like Properties in Chronic Animal Model of Multiple Sclerosis.
abstract: 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 α-linolenic acid and linoleic acid metabolism (PUFA). The metabolites of PUFAs, including ω-3 and ω-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 of ω-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.
authors.affiliation: From the Center for Bioinformatics and Departments of Public Health Sciences and.
authors.forename: Laila M
authors.initials: LM
authors.lastname: Poisson
authors.affiliation: Neurology, and.
authors.forename: Hamid
authors.initials: H
authors.lastname: Suhail
authors.affiliation: Neurology, and.
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Singh
authors.affiliation: From the Center for Bioinformatics and Departments of Public Health Sciences and.
authors.forename: Indrani
authors.initials: I
authors.lastname: Datta
authors.affiliation: the Departments of Neurology and.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Denic
authors.affiliation: the Department of Pharmacology, Medical University of Silesia, Medyków 18, PL 40-752 Katowice, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Labuzek
authors.affiliation: the Department of Neurology, Georgia Health Sciences University, Augusta, Georgia 30912, the Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia 30912.
authors.forename: Md Nasrul
authors.initials: MN
authors.lastname: Hoda
authors.affiliation: Neurology, and.
authors.forename: Ashray
authors.initials: A
authors.lastname: Shankar
authors.affiliation: the Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, Michigan 48202.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Neurology, and.
authors.forename: Mirela
authors.initials: M
authors.lastname: Cerghet
authors.affiliation: Neurology, and.
authors.forename: Stanton
authors.initials: S
authors.lastname: Elias
authors.affiliation: Metabolon, Inc., Durham, North Carolina 27713, and.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mohney
authors.affiliation: the Departments of Neurology and Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55906.
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
authors.affiliation: Division of Gynecology Oncology, Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202.
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Rattan
authors.affiliation: the Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Mangalam
authors.affiliation: Neurology, and SGiri1@hfhs.org.
authors.forename: Shailendra
authors.initials: S
authors.lastname: Giri
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D053858:Metabolic Networks and Pathways; D055432:Metabolomics; D051379:Mice; D009103:Multiple Sclerosis / Q000378:metabolism*; D010949:Plasma / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005231:Fatty Acids, Unsaturated
keywords: autoimmune disease; inflammation; metabolism; metabolomics; multiple sclerosis; neuroinflammation