Potential MS Therapeutic Targets Found in Plasma Metabolites

In a new study entitled “Untargeted plasma metabolomics identifies endogenous metabolite with drug-like properties in chronic animal model of multiple sclerosis,” a team of researchers performed a comparative analysis of metabolites between control mice and a mouse model with experimental autoimmune encephalitis (EAE, the most commonly used experimental model for the human inflammatory demyelinating disease, multiple sclerosis). The team identified EAE-specific alterations in metabolites, therefore suggesting their potential importance in multiple sclerosis (MS) pathogenesis. The study was published in The Journal of Biological Chemistry.

Metabolic alterations have been reported in several diseases as either potential disease biomarkers or therapeutic targets. In fact, recent metabolomics studies (aiming at understating the set of metabolites present within an organism, cell, or tissue) identified potential disease biomarkers in neurological diseases, including Alzheimer’s disease, Parkinson’s disease, and in animal models of MS.

Here, authors performed a metabolomics analysis on plasma from a EAE mouse model. The analysis was conducted at the chronic phase of the disease with the goal of identifying if this phase was associated with a unique metabolic profile when compared with control mice.

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The team identified, out of 324 metabolites analyzed, 100 metabolites as significantly altered between the EAE mice and controls. The identified molecules spanned different metabolic classes and pathways, being identified as lipids, amino acid, peptide, xenobiotic, carbohydrate, nucleotide and energy pathways. Researchers observed that the majority of the metabolic alterations in EAE mice occurred in lipids. Of note, bioinformatic analysis showed that six of the metabolic pathways altered in EAE mice included alpha linolenic acid and linoleic acid metabolism, both polyunsaturated fatty acids (PUFAs). The metabolism of the PUFA pathway (which includes omega-3 and omega-6 fatty acids) was found to be down-regulated in the plasma of EAE. In fact, PUFA metabolites were previously identified as being decreased in mouse models of MS and in MS patients.

The team performed further studies to identify what was the biological relevance for MS disease of a down-regulation of omega-3. To this end, researchers administered EAE mice with a daily oral dose of resolvin D1, a downstream metabolite of omega-3. Authors observed that resolvin D1 decreased disease progression by inhibiting the rise of autoreactive T cells. Moreover, the team found that resolvin D1 induced a population of macrophages that is involved in tissue repair and anti-inflammatory responses. Hence, resolvin D1 acts by reducing the pro-inflammatory environment in the central nervous system of EAE mice.

The team highlights that using a metabolomics approach can identify potential therapeutic targets or metabolites that may protect against MS, such as resolvin D1.