Systemic Acrolein Elevations in Mice With Experimental Autoimmune Encephalomyelitis and Patients With Multiple Sclerosis.

Melissa Tully,Riyi Shi,Lingxing Zheng,Lee Hayward,Ran Tian,David Mattson,Nicholas Race,Jonathan Tang,Glen Acosta

doi:10.3389/fneur.2018.00420

Abstract

Demyelination and axonal injury are the key pathological processes in multiple sclerosis (MS), driven by inflammation and oxidative stress. Acrolein, a byproduct and instigator of oxidative stress, has been demonstrated as a neurotoxin in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, due to the invasive nature of acrolein detection using immunoblotting techniques, the investigation of acrolein in MS has been limited to animal models. Recently, detection of a specific acrolein-glutathione metabolite, 3-HPMA, has been demonstrated in urine, enabling the noninvasive quantification of acrolein for the first time in humans with neurological disorders. In this study, we have demonstrated similar elevated levels of acrolein in both urine (3-HPMA) and in spinal cord tissue (acrolein-lysine adduct) in mice with EAE, which can be reduced through systemic application of acrolein scavenger hydralazine. Furthermore, using this approach we have demonstrated an increase of 3-HPMA in both the urine and serum of MS patients relative to controls. It is expected that this noninvasive acrolein detection could facilitate the investigation of the role of acrolein in the pathology of MS in human. It may also be used to monitor putative therapies aimed at suppressing acrolein levels, reducing severity of symptoms, and slowing progression as previously demonstrated in animal studies.

Highlights

Multiple sclerosis (MS) is a presumed autoimmune demyelinating central nervous system disease that affects approximately 2.5 million people worldwide [1]
Systemic acrolein levels based on urine samples in EAE mouse were determined through the quantification of 3-hydroxypropyl mercapturic acid (3-HPMA) using liquid chromatography (LC)/multiple sclerosis (MS)/MS [27]
At days 7–9, EAE mice displayed an elevated level of 3-HPMA (27.3 ± 4.2 μg/mg creatinine) which is significantly higher than control mice (16.9 ± 0.8 μg/mg creatinine, p < 0.05)

Summary

Introduction

Multiple sclerosis (MS) is a presumed autoimmune demyelinating central nervous system disease that affects approximately 2.5 million people worldwide [1]. Attenuation of acrolein through treatment of EAE with hydralazine, an FDA-approved anti-hypertensive that is known to be an acrolein scavenger [16, 17, 19,20,21,22,23], resulted in a reduction of central nervous system (CNS) acrolein levels which correlated with improved behavioral outcomes and delayed symptomatic onset in EAE mice [12]. These data suggest a pathogenic role of acrolein in EAE. Clinical determination of acrolein levels in vivo in MS patients has not been conducted due to technical difficulties

Methods

Results

Conclusion