Neuroprotective Effect of Glatiramer Acetate on Neurofilament Light Chain Leakage and Glutamate Excess in an Animal Model of Multiple Sclerosis.

Rina Aharoni,Ruth Arnon,Amir Dori,Efrat Shavit-Stein,Raya Eilam,Joab Chapman,Shaul Lerner

doi:10.3390/ijms222413419

Abstract

Axonal and neuronal pathologies are a central constituent of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), induced by the myelin oligodendrocyte glycoprotein (MOG) 35–55 peptide. In this study, we investigated neurodegenerative manifestations in chronic MOG 35–55 induced EAE and the effect of glatiramer acetate (GA) treatment on these manifestations. We report that the neuronal loss seen in this model is not attributed to apoptotic neuronal cell death. In EAE-affected mice, axonal damage prevails from the early disease phase, as revealed by analysis of neurofilament light (NFL) leakage into the sera along the disease duration, as well as by immunohistological examination. Elevation of interstitial glutamate concentrations measured in the cerebrospinal fluid (CSF) implies that glutamate excess plays a role in the damage processes inflicted by this disease. GA applied as a therapeutic regimen to mice with apparent clinical symptoms significantly reduces the pathological manifestations, namely apoptotic cell death, NFL leakage, histological tissue damage, and glutamate excess, thus corroborating the neuroprotective consequences of this treatment.

Highlights

IntroductionIn multiple sclerosis (MS) and its animal model, experimental autoimmune encephalo myelitis (EAE), the immune system (including T-cells, B-cells, and components of the innate immune system) reacts against the myelin envelope that surrounds the axons, resulting in demyelination and tissue damage [1–3]
In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalo myelitis (EAE), the immune system reacts against the myelin envelope that surrounds the axons, resulting in demyelination and tissue damage [1–3]
When cortical gray matter brain sections were double stained for Caspase-3 and the neuronal marker neuronal-specific nuclear protein (NeuN), only a few Caspase-3 positive cells could be detected, and these cells were negative for the neuronal marker NeuN (Figure 1C, upper row)

Summary

Introduction

In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalo myelitis (EAE), the immune system (including T-cells, B-cells, and components of the innate immune system) reacts against the myelin envelope that surrounds the axons, resulting in demyelination and tissue damage [1–3]. MS is increasingly acknowledged as a neurodegenerative disease triggered by an inflammatory attack on the CNS [6–8] While both inflammation and demyelination are well recognized, the processes involved in neurodegeneration are less defined. The ultimate consequence of the degenerative process, cognitive deterioration, was manifested in this model by impairments in working and long-term memory, starting at the early stages and increasing with disease progression [12]. These characteristics are either absent or less prominent in other EAE models, such as the relapsing remitting EAE model induced by the myelin proteolipid protein (PLP) 139–151 peptide in SJL/J mice [9,11]

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