HPLC-MS/MS Oxylipin Analysis of Plasma from Amyotrophic Lateral Sclerosis Patients.

Mauricio Mastrogiovanni,Mònica Povedano,Homero Rubbo,Hugo Naya,Carla Marco,Andrés Trostchansky,Rubèn López-Vales,Raúl Dominguez

doi:10.3390/biomedicines10030674

Abstract

Oxylipins play a critical role in regulating the onset and resolution phase of inflammation. Despite inflammation is a pathological hallmark in amyotrophic lateral sclerosis (ALS), the plasma oxylipin profile of ALS patients has not been assessed yet. Herein, we develop an oxylipin profile-targeted analysis of plasma from 74 ALS patients and controls. We found a significant decrease in linoleic acid-derived oxylipins in ALS patients, including 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE. These derivatives have been reported as important regulators of inflammation on different cell systems. In addition, some 5-lipoxygenase metabolites, such as 5-hydroxy- eicosatetraenoic acid also showed a significant decrease in ALS plasma samples. Isoprostanes of the F2α family were detected only in ALS patients but not in control samples, while the hydroxylated metabolite 11-HETE significantly decreased. Despite our effort to analyze specialized pro-resolving mediators, they were not detected in plasma samples. However, we found the levels of 14-hydroxy-docosahexaenoic acid, a marker pathway of the Maresin biosynthesis, were also reduced in ALS patients, suggesting a defective activation in the resolution programs of inflammation in ALS. We further analyze oxylipin concentration levels in plasma from ALS patients to detect correlations between these metabolites and some clinical parameters. Interestingly, we found that plasmatic levels of 13-HODE and 9-HODE positively correlate with disease duration, expressed as days since onset. In summary, we developed a method to analyze “(oxy)lipidomics” in ALS human plasma and found new profiles of metabolites and novel lipid derivatives with unknown biological activities as potential footprints of disease onset.

Highlights

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons, leading to motor and extra-motor symptoms [1]
A misbalance in pro- and anti-inflammatory and pro-resolving lipid mediators could play a critical role in neuroinflammation associated with ALS disease
Despite some eviplay a critical role in neuroinflammation associated with ALS disease

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons, leading to motor and extra-motor symptoms [1]. The cause of ALS is unknown, some individuals have a family antecedent, which is associated with mutations in genes that have a wide range of roles. Some of the implicated genes are incompletely penetrant in familial ALS, and with rare exceptions, genotype does not necessarily predict phenotype [1]. As is the case with other neurodegenerative diseases, it is recognized that ALS is a heterogeneous condition associated with more than one pathogenic mechanism and with different clinical characteristics [2]. Degeneration of motor neurons is accompanied by neuroinflammatory processes, with the proliferation of astroglia, microglia, and oligodendroglia [3]. Neuroinflammation has been observed by imaging studies in patients with

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Conclusion