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Caractérisation des activités cytoprotectrices de molécules utilisées dans le traitement de la sclérose en plaques (diméthyle fumarate, monométhyle fumarate, biotine) sur des oligodendrocytes 158N : impact sur le stress oxydant, le statut mitochondrial, le statut lipidique, l’apoptose et l’autophagie

Abstract : Oxidative stress, mitochondrial dysfunction, and alterations in lipid metabolism are a common denominator of neurodegenerative diseases (MN), such as multiple sclerosis (MS). Under oxidative stress conditions, excess cholesterol is removed by oxidation, producing oxysterols. In humans, the 7β-hydroxycholesterol (7β-OHC) is often found at increased levels in the cerebrospinal fluid (CSF) and/or plasma of patients with MN, including MS.In this context, a preliminary clinical study on CSF and plasma of patients with RR MS was carried out to search for lipid metabolism and oxidative stress biomarkers and to determine the possible correlations between 7β-OHC and the different mechanisms associated with the MS pathogenesis. An in vitro study was conducted to evaluate the biological activities of three molecules used in the treatment of MS, dimethyl fumarate (DMF) and its major metabolite, monomethyl fumarate (MMF), and biotin on 158N murine oligodendrocytes, and to determine their cytoprotective potentialities by focusing on their ability to oppose the toxicity of 7β-OHC. For this, spectrophotometric, analytical and molecular biology techniques were used.Our results have shown an increased level of HODE associated with an enhancement of oxysterol levels in the plasma, notably 7KC and 7β-OHC, as well an alteration in fatty acid metabolism in the CSF and plasma of patients with SEP. The in vitro study revealed that DMF, MMF, and biotin can counteract the deleterious effects of 7β-OHC namely; cell death by oxiapoptophagy defined by the association of apoptosis, autophagy and oxidative stress. Moreover, these molecules correct the structural modifications and the disequilibrium of the redox status characterized by an overproduction of radical oxygen species, an increased activity of the principal antioxidant enzymes and an amplification of the macromolecules oxidation induced by the 7β- OHC. They also attenuate the mitochondrial and peroxisomal dysfunctions, the alterations of myelin protein expression as well as the lipid profile disorder induced by 7β-OHC.Our study provides arguments in favor of the ability of DMF, MMF, and biotin, to attenuate the major events associated with the death of oligodendrocytes which could contribute to demyelination. This reinforces the interest in these molecules for the treatment of neurodegenerative diseases including MS.
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Randa Sghaier. Caractérisation des activités cytoprotectrices de molécules utilisées dans le traitement de la sclérose en plaques (diméthyle fumarate, monométhyle fumarate, biotine) sur des oligodendrocytes 158N : impact sur le stress oxydant, le statut mitochondrial, le statut lipidique, l’apoptose et l’autophagie. Biologie moléculaire. Université Bourgogne Franche-Comté; Faculté des sciences, université de Monastir, Tunisie, 2019. Français. ⟨NNT : 2019UBFCK048⟩. ⟨tel-02402119⟩

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