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The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators

Multiple sclerosis (MS) is an inflammatory, demyelinating disease with an unknown origin. Previous studies showed the involvement of the hypothalamic–pituitary–adrenal (HPA) axis to susceptibility to autoimmune diseases, including MS, and its best-characterized animal model, experimental autoimmune...

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Autores principales: Trifunovic, Svetlana, Stevanovic, Ivana, Milosevic, Ana, Ristic, Natasa, Janjic, Marija, Bjelobaba, Ivana, Savic, Danijela, Bozic, Iva, Jakovljevic, Marija, Tesovic, Katarina, Laketa, Danijela, Lavrnja, Irena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248369/
https://www.ncbi.nlm.nih.gov/pubmed/34220419
http://dx.doi.org/10.3389/fnins.2021.649485
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author Trifunovic, Svetlana
Stevanovic, Ivana
Milosevic, Ana
Ristic, Natasa
Janjic, Marija
Bjelobaba, Ivana
Savic, Danijela
Bozic, Iva
Jakovljevic, Marija
Tesovic, Katarina
Laketa, Danijela
Lavrnja, Irena
author_facet Trifunovic, Svetlana
Stevanovic, Ivana
Milosevic, Ana
Ristic, Natasa
Janjic, Marija
Bjelobaba, Ivana
Savic, Danijela
Bozic, Iva
Jakovljevic, Marija
Tesovic, Katarina
Laketa, Danijela
Lavrnja, Irena
author_sort Trifunovic, Svetlana
collection PubMed
description Multiple sclerosis (MS) is an inflammatory, demyelinating disease with an unknown origin. Previous studies showed the involvement of the hypothalamic–pituitary–adrenal (HPA) axis to susceptibility to autoimmune diseases, including MS, and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). During MS/EAE, innate immune cells are activated and release cytokines and other inflammatory mediators, leading to a vicious cycle of inflammation. In response to inflammation, the activated HPA axis modulates immune responses via glucocorticoid activity. Because the mechanisms involving oxidative stress to the HPA axis are relatively unrevealed, in this study, we investigate the inflammatory and oxidative stress status of HPA axis during EAE. Our results reveal an upregulation of Pomc gene expression, followed by POMC and ACTH protein increase at the peak of the EAE in the pituitary. Also, prostaglandins are well-known contributors of HPA axis activation, which increases during EAE at the periphery. The upregulated Tnf expression in the pituitary during the peak of EAE occurred. This leads to the activation of oxidative pathways, followed by upregulation of inducible NO synthase expression. The reactive oxidant/nitrosative species (ROS/RNS), such as superoxide anion and NO, increase their levels at the onset and peak of the disease in the pituitary and adrenal glands, returning to control levels at the end of EAE. The corticotrophs in the pituitary increased in number and volume at the peak of EAE that coincides with high lipid peroxidation levels. The expression of MC2R in the adrenal glands increases at the peak of EAE, where strong induction of superoxide anion and malondialdehyde (MDA), reduced total glutathione (GSH) content, and catalase activity occurred at the peak and end of EAE compared with controls. The results obtained from this study may help in understanding the mechanisms and possible pharmacological modulation in MS and demonstrate an effect of oxidative stress exposure in the HPA activation during the course of EAE.
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spelling pubmed-82483692021-07-02 The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators Trifunovic, Svetlana Stevanovic, Ivana Milosevic, Ana Ristic, Natasa Janjic, Marija Bjelobaba, Ivana Savic, Danijela Bozic, Iva Jakovljevic, Marija Tesovic, Katarina Laketa, Danijela Lavrnja, Irena Front Neurosci Neuroscience Multiple sclerosis (MS) is an inflammatory, demyelinating disease with an unknown origin. Previous studies showed the involvement of the hypothalamic–pituitary–adrenal (HPA) axis to susceptibility to autoimmune diseases, including MS, and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). During MS/EAE, innate immune cells are activated and release cytokines and other inflammatory mediators, leading to a vicious cycle of inflammation. In response to inflammation, the activated HPA axis modulates immune responses via glucocorticoid activity. Because the mechanisms involving oxidative stress to the HPA axis are relatively unrevealed, in this study, we investigate the inflammatory and oxidative stress status of HPA axis during EAE. Our results reveal an upregulation of Pomc gene expression, followed by POMC and ACTH protein increase at the peak of the EAE in the pituitary. Also, prostaglandins are well-known contributors of HPA axis activation, which increases during EAE at the periphery. The upregulated Tnf expression in the pituitary during the peak of EAE occurred. This leads to the activation of oxidative pathways, followed by upregulation of inducible NO synthase expression. The reactive oxidant/nitrosative species (ROS/RNS), such as superoxide anion and NO, increase their levels at the onset and peak of the disease in the pituitary and adrenal glands, returning to control levels at the end of EAE. The corticotrophs in the pituitary increased in number and volume at the peak of EAE that coincides with high lipid peroxidation levels. The expression of MC2R in the adrenal glands increases at the peak of EAE, where strong induction of superoxide anion and malondialdehyde (MDA), reduced total glutathione (GSH) content, and catalase activity occurred at the peak and end of EAE compared with controls. The results obtained from this study may help in understanding the mechanisms and possible pharmacological modulation in MS and demonstrate an effect of oxidative stress exposure in the HPA activation during the course of EAE. Frontiers Media S.A. 2021-06-17 /pmc/articles/PMC8248369/ /pubmed/34220419 http://dx.doi.org/10.3389/fnins.2021.649485 Text en Copyright © 2021 Trifunovic, Stevanovic, Milosevic, Ristic, Janjic, Bjelobaba, Savic, Bozic, Jakovljevic, Tesovic, Laketa and Lavrnja. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Trifunovic, Svetlana
Stevanovic, Ivana
Milosevic, Ana
Ristic, Natasa
Janjic, Marija
Bjelobaba, Ivana
Savic, Danijela
Bozic, Iva
Jakovljevic, Marija
Tesovic, Katarina
Laketa, Danijela
Lavrnja, Irena
The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators
title The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators
title_full The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators
title_fullStr The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators
title_full_unstemmed The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators
title_short The Function of the Hypothalamic–Pituitary–Adrenal Axis During Experimental Autoimmune Encephalomyelitis: Involvement of Oxidative Stress Mediators
title_sort function of the hypothalamic–pituitary–adrenal axis during experimental autoimmune encephalomyelitis: involvement of oxidative stress mediators
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248369/
https://www.ncbi.nlm.nih.gov/pubmed/34220419
http://dx.doi.org/10.3389/fnins.2021.649485
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