Memantine Modulates Oxidative Stress in the Rat Brain following Experimental Autoimmune Encephalomyelitis.

Beata Dąbrowska-Bouta,Grzegorz Sulkowski,Marta Sidoryk-Węgrzynowicz,Lidia Strużyńska

doi:10.3390/ijms222111330

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an animal model most commonly used in research on the pathomechanisms of multiple sclerosis (MS). The inflammatory processes, glutamate excitotoxicity, and oxidative stress have been proposed as determinants accompanying demyelination and neuronal degeneration during the course of MS/EAE. The aim of the current study was to characterize the role of NMDA receptors in the induction of oxidative stress during the course of EAE. The effect of memantine, the uncompetitive NMDA receptor antagonist, on modulation of neurological deficits and oxidative stress in EAE rats was analyzed using several experimental approaches. We demonstrated that the expression of antioxidative enzymes (superoxide dismutases SOD1 and SOD2) were elevated in EAE rat brains. Under the same experimental conditions, we observed alterations in oxidative stress markers such as increased levels of malondialdehyde (MDA) and decreased levels of sulfhydryl (-SH) groups, both protein and non-protein (indicating protein damage), and a decline in reduced glutathione. Importantly, pharmacological inhibition of ionotropic NMDA glutamate receptors by their antagonist memantine improved the physical activity of EAE rats, alleviated neurological deficits such as paralysis of tail and hind limbs, and modulated oxidative stress parameters (MDA, -SH groups, SOD’s). Furthermore, the current therapy aiming to suppress NMDAR-induced oxidative stress was partially effective when NMDAR’s antagonist was administered at an early (asymptomatic) stage of EAE.

Highlights

Experimental autoimmune encephalomyelitis (EAE) is the most popular and well characterized animal model of multiple sclerosis (MS)
We analyzed the effect of the uncompetitive NMDA receptor antagonist, memantine, on the selective parameters of oxidative stress and neurological deficits in EAE rats
We demonstrated that administration of memantine: (i) significantly decreases the level of MDA relative to untreated EAE rats; (ii) significantly prevents the decrease in non-protein-SH groups and slightly increases the levels of total protein and protein–SH groups at a peak of the disease; (iii) increases expression of SOD1 protein relative to untreated EAE rats; (iv) significantly increases SOD activity compared to untreated

Summary

Introduction

Experimental autoimmune encephalomyelitis (EAE) is the most popular and well characterized animal model of multiple sclerosis (MS). The characteristic features of the disease are demyelinating areas in the white and grey matter of the spinal cord and brain. The presence of lymphocytes, macrophages and activated microglia has been observed in the proximity of the perivascular area [2,3], suggesting that these types of cells are involved in the process of demyelination [4]. Macrophages and reactive microglia activate the complement pathway, produce pro-inflammatory cytokines, release excitatory amino acids, and generate free radicals [2]. All of these factors can damage myelin and oligodendrocytes and, disrupt neurotransmission or induce injury and death of neurons. Inflammation, glutamate excitotoxicity and oxidative stress have all been proposed as the most important determi-

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