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Oxidative Stress and Lymphocyte Alterations in Chronic Relapsing Experimental Allergic Encephalomyelitis in the Rat Hippocampus and Protective Effects of an Ethanolamine Phosphate Salt

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Abstract

Chronic relapsing experimental allergic encephalomyelitis (CR-EAE) exhibits neuropathological and immunological dysfunctions similar to those found in multiple sclerosis (MS) and has been used as an animal model of MS. Inflammatory infiltrates and oxidative stress have been linked to the development of both diseases. Ethanolamine plasmalogen derivates have been shown to be powerful antioxidants and immunomodulators. Therefore, the objective of this study was to analyse inflammatory infiltrates, the state of the oxidative defences and the possible protective effects of calcium, magnesium and phosphate ethanolamine (EAP) in the CR-EAE rat hippocampus. To this aim, we evaluated, by immunohistochemistry, T cell infiltrates, Iba-1+ (a marker of activated microglia) immunoreactivity and TUNEL (+) cells. We also measured the protein levels and activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GP) and glutathione reductase (GR). In addition, reduced (GSH) and oxidized (GSSG) glutathione levels, lipid peroxidation and cholesterol as well as desmosterol content were determined. We found an increase in T cell infiltrates and Iba1+ immunoreactivity, lipid peroxidation, SOD, GP and GR activities as well as enhanced cholesterol levels and a decrease in CAT activity, GSH and desmosterol levels in the first and second attack in the CR-EAE rat hippocampus. Pretreatment of CR-EAE rats with EAP led to a delay in the onset of the clinical signs of the disease as well as a decrease in inflammatory infiltrates and alterations of the antioxidant defences in the hippocampus. Altogether, the present results suggest a protective role of EAP in the CR-EAE rat hippocampus.

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Acknowledgments

We wish to thank the staff of the Animal Center of the Universidad de Alcalá for their support with the animal care and handling. CIBEROBN is an initiative of the Instituto de Salud Carlos III (ISCIII), Spain. MOIR Mechanisms of Insulin Resistance.

Funding

This work was supported by the Ministerio de Ciencia e Innovación (SAF2010-22277), (SAF2011-29951) and (S2010/BMD-2423).

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Authors and Affiliations

  1. Grupo de Neurobioquímica, Unidad de Bioquímica y Biología Molecular, Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain

    Aranzazu Perianes-Cachero, Alberto M. Hernández-Pinto, Eduardo Arilla-Ferreiro & Lilian Puebla-Jiménez

  2. Departamento de Biomedicina y Biotecnología, Unidad de Biología Celular, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain

    María V. T. Lobo

  3. 3D Lab (Development, Differentiation & Degeneration), Centro de Investigaciones Biológicas (CIB-CSIC), C/Ramiro de Maeztu 9, 28040, Madrid, Spain

    Alberto M. Hernández-Pinto

  4. Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, IRYCIS, Ctra. Colmenar Km 9, 28034, Madrid, Spain

    Rebeca Busto & Miguel Angel Lasunción-Ripa

  5. CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, Madrid, Spain

    Rebeca Busto & Miguel Angel Lasunción-Ripa

Authors
  1. Aranzazu Perianes-Cachero
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  2. María V. T. Lobo
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  3. Alberto M. Hernández-Pinto
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  4. Rebeca Busto
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  5. Miguel Angel Lasunción-Ripa
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  6. Eduardo Arilla-Ferreiro
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  7. Lilian Puebla-Jiménez
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Corresponding author

Correspondence to Lilian Puebla-Jiménez.

Ethics declarations

The animal experiments performed in the present study conform to the guidelines set by the Animal Care Committee of Alcalá University as well as to the International guidelines on the ethical use of animals set by the Council of Europe (Protection of Animals Used for Experimentation, 1986 ETS No. 123), and all experimental protocols were previously approved.

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Electronic Supplementary Material

Supplementary Fig. 1

The image shows the cutting plane of the brain of control rats, rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE), rats with CR-EAE pre-treated with a calcium, magnesium and phosphate ethanolamine salt (EAP) and control rats pre-treated with EAP used to evaluate the infiltrates and activation of T cells, Iba1+ cells, IgG levels and TUNEL(+) cells in the hippocampus. This study has been carried out in similar areas of the medial section of the hippocampus rostro-caudal axis. (PPTX 5810 kb)

Supplementary Fig. 2

CD3+ and CD8+ cells. Immunohistochemical labelling of CD3+ and CD8+ cell infiltrates in the hippocampus of rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) at three phases of the disease: first relapse, remission and second relapse, and effects of an EAP salt. The scale bar: 500 μm and 100 μm. The figure shows the most representative images of five independent stains of the hippocampal sagittal section of rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) and effects of an EAP salt. (PPTX 650 kb)

Supplementary Fig. 3

Iba1+ cells. Panel A: Immunohistochemical labelling of Iba1+ cells in the hippocampus of rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) at three phases of the disease: first relapse, remission and second relapse, and effects of an EAP salt. The scale bar: 100 μm. Panel B: Immunohistochemical labelling of Iba1+ cells and the score used to determine the degree of activation in the hippocampus. The scale bar: 50 μm. The figure shows the most representative images of five independent stains of the hippocampal sagittal section of rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) and effects of an EAP salt. (PPTX 2012 kb)

Supplementary Fig. 4

Ig G levels. in the hippocampus of rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) at three phases of the disease, and effects of EAP salt. Immunohistochemical labelling of IgG levels in the hippocampus of rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) at three phases of the disease: first relapse, remission and second relapse, and effects of an EAP salt. The scale bar: 500 μm. The figure shows the most representative images of five independent stains of the sagittal section of the hippocampus of rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) and effects of an EAP salt. (PPTX 455 kb)

Supplementary Fig. 5

TUNEL (+) cells. Immunohistochemical labelling of TUNEL (+) cells in the hippocampus of rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) at three phases of the disease; first relapse, remission and second relapse, and effects of an EAP salt. The scale bar: 500 μm and 50 μm. The figure shows the most representative images of five independent stains of the sagittal section of the hippocampus of rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) and effects of an EAP salt. (PPTX 546 kb)

Supplementary Fig. 6

The diagram depicts the alterations in the antioxidant defences and the possible mechanism of action of an ethanolamine phosphate salt (EAP) in the hippocampus of rats with chronic relapsing experimental allergic encephalomyelitis (CR-EAE) at the first attack. Panel A: In rats with CR-EAE, the increase of CD3+ cells, TNF-α and IFN-γ levels in the rat hippocampus enhances the amount and activation of resident Iba- 1+ cells. These cells begin to produce reactive oxygen species in the hippocampus. The alterations in the activity and quantity of enzymes involved in antioxidant defence also contribute to cell dysfunction. Our results showed an increase in the amount and activity of superoxide dismutase (SOD),a decrease in the amount and activity of catalase (CAT) and an impairment in the glutathione system (glutathione peroxidase (GP) and glutathione reductase (GR)). These alterations might contribute to the increase of lipid peroxidation and a dysfunction in the cellular activities of the hippocampus. Panel B: The CR-EAE + EAP rats show a decrease in the number of CD3+ cells in the hippocampus and less amount and activation of microglial cells, which involves a decrease in the number of oxidative radicals and lower levels of TNF-α. We have shown that the amount and activity of the antioxidant enzymes SOD, CAT, and the glutathione system (GR and GP) remain stable. All these findings could explain that in the CR-EAE + EAP rats, there is less lipid peroxidation and an improvement in the cellular activities of the hippocampus when compared with EAE-CR at the first attack. (PPTX 2123 kb)

Supplementary Fig. 7

The diagram depicts the alterations in the antioxidant defences and the possible mechanism of action of an ethanolamine phosphate salt (EAP) in the hippocampus of rats with CR-EAE at the second attack. Panel A: In the second relapse of CR-EAE, the amount of CD3+ cells and the amount and activity of Iba1+ cells are higher than in the first relapse. The increase in TNF-α levels in these rats could induce alterations in mitochondrial function that involve an increase of ROS and RNS. In addition, the alterations in the activity and amount of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and the impairment of the glutathione system (glutathione peroxidase (GP) and glutathione reductase (GR)) could contribute to the increase of lipid peroxidation, DNA damage and a dysfunction in the cellular activities of the hippocampus. Panel B: The EAP salt, in rats with CR-EAE, could reduce the alterations of cellular activities in the hippocampus by different mechanisms: these rats show a decrease in the number of CD3+ cells and less reduction in the amount and activation of microglial cells, which involves a decrease in the number of oxidative radicals and lower TNF-α levels. The present study also shows that the amount and activity of the antioxidant enzymes SOD, CAT, and the glutathione system (GR and GP) remain stable. (PPTX 2322 kb)

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Perianes-Cachero, A., Lobo, M.V.T., Hernández-Pinto, A.M. et al. Oxidative Stress and Lymphocyte Alterations in Chronic Relapsing Experimental Allergic Encephalomyelitis in the Rat Hippocampus and Protective Effects of an Ethanolamine Phosphate Salt. Mol Neurobiol 57, 860–878 (2020). https://doi.org/10.1007/s12035-019-01774-8

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