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Thèse De Doctorat THÈSE DE DOCTORAT Évaluation de l’influence de stilbènes sélectionnés sur la neuroprotection contre l’AVC avec un focus sur la signalisation inflammatoire Veronika LELÁKOVÁ Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, UMR7275 Département de Pharmacie Moléculaire, Faculté de Pharmacie, Université Masaryk Présentée en vue de l’obtention du Devant le jury, composé de : grade de docteur en Sciences de la Vie et Karel Šmejkal, Prof. Assoc., MUNI, CZ de la Santé d’Université Côte d’Azur et du Maria-Grazia De Simoni, Prof., IRCCS, IT grade de docteur d’Université Masaryk Pavel Babica, Prof. Assoc., MUNI, CZ Dirigée par : Dr. Catherine Heurteaux / Václav Suchý, Prof., MUNI, CZ Prof. Assoc. Jan Hošek Catherine Heurteaux, DR CNRS, IPMC, FR Soutenue le : 15 décembre 2020 à Brno, Jan Hošek, Prof. Assoc., UPOL, CZ Université Masaryk Nicolas Blondeau, DR CNRS, IPMC, FR DISSERTATION THESIS Evaluation of the influence of selected stilbenes on neuroprotection against stroke with a focus on inflammatory signaling Veronika LELÁKOVÁ Institute of Molecular and Cellular Pharmacology, CNRS, UMR7275 Department of Molecular Pharmacy, Faculty of Pharmacy, Masaryk University Presented for the purpose of obtaining In front of the jury composed of : the degree of Doctor in Life and Health Karel Šmejkal, Assoc. Prof., MUNI, CZ Sciences from University Côte d’Azur and Maria-Grazia De Simoni, Prof., IRCCS, IT the degree of Doctor from Masaryk University Pavel Babica, Assoc. Prof., MUNI, CZ Supervised by: Dr. Catherine Heurteaux / Václav Suchý, Prof., MUNI, CZ Assoc. Prof. Jan Hošek Catherine Heurteaux, DR CNRS, IPMC, FR Defended: 15th December 2020 in Brno, Jan Hošek, Assoc. Prof., UPOL, CZ Masaryk University Nicolas Blondeau, DR CNRS, IPMC, FR Évaluation de l’influence de stilbènes sélectionnés sur la neuroprotection contre l’AVC avec un focus sur la signalisation inflammatoire Jury: Président du jury Karel Šmejkal, Professeur associé, Université Masaryk (MUNI), Faculté de Pharmacie, Département des médicaments naturels, Brno, République tchèque Rapporteurs Maria-Grazia De Simoni, Professeur, Laboratoire de l’inflammation et des maladies du système nerveux, Institut de Recherche Pharmacologique Mario Negri, Milan, Italie Pavel Babica, Professeur associé, Université Masaryk (MUNI), Faculté de Science, RECETOX, Brno, République tchèque Examinateur Václav Suchý, Professeur, Université Masaryk (MUNI), Faculté de Pharmacie, Département des médicaments naturels, Brno, République tchèque Directeurs de thèse Catherine Heurteaux, Directeur de Recherche (DR1 CNRS), Université Côte D’Azur (UCA), Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), CNRS UMR7275, Valbonne, France Jan Hošek, Professeur associé, Université Palacký à Olomouc (UPOL), Faculté de Science, Centre régional des technologies et matériaux avancés, Division des complexes biologiquement actifs et des aimants moléculaires, Olomouc, République tchèque Consultant de thèse Nicolas Blondeau, Directeur de Recherche (DR2 CNRS), Université Côte D’Azur (UCA), Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), CNRS UMR7275, Valbonne, France Evaluation of the influence of selected stilbenes on neuroprotection against stroke with a focus on inflammatory signaling Jury: President of jury Karel Šmejkal, Associate Professor (Docent), Masaryk University (MUNI), Faculty of Pharmacy, Department of Natural Drugs, Brno, Czech Republic Opponents Maria-Grazia De Simoni, Professor, Laboratory of Inflammation and Nervous System Diseases, Mario Negri Institute for Pharmacological Research (Istituto di Ricerche Farmacologiche Mario Negri IRCCS), Milan, Italy Pavel Babica, Associate Professor (Docent), Masaryk University (MUNI), Faculty of Science, RECETOX, Brno, Czech Republic Examiner Václav Suchý, Professor, Masaryk University (MUNI), Faculty of Pharmacy, Department of Natural Drugs, Brno, Czech Republic Thesis supervisors Catherine Heurteaux, Director of Research (DR1 CNRS), University Côte D’Azur (UCA), Institute of Molecular and Cellular Pharmacology (IPMC), CNRS UMR7275, Valbonne, France Jan Hošek, Associate Professor (Docent), Palacký University in Olomouc (UPOL), Faculty of Science, Regional Centre of Advanced Technologies and Materials, Division of Biologically Active Complexes and Molecular Magnets, Olomouc, Czech Republic Thesis consultant Nicolas Blondeau, Director of Research (DR2 CNRS), University Côte D’Azur (UCA), Institute of Molecular and Cellular Pharmacology (IPMC), CNRS UMR7275, Valbonne, France Bibliographic record Author: PharmDr. Veronika Leláková MASARYK UNIVERSITY (MUNI) Faculty of Pharmacy, Department of Molecular Pharmacy Palackého třída 1946/1, 61200 Brno, Czech Republic UNIVERSITÉ CÔTE D’AZUR (UCA) École doctorale des Sciences de la Vie et de la Santé Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR7275, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France Title of Thesis: Evaluation of the influence of selected stilbenes on neuroprotection against stroke with a focus on inflammatory signaling (ENG) Hodnocení vlivu vybraných stilbenů na neuroprotekci u cévní mozkové příhody se zaměřením na zánětlivou signalizaci (CZ) Évaluation de l’influence de stilbènes sélectionnés sur la neuroprotection contre l’AVC avec un focus sur la signalisation inflammatoire (FR) Degree Program: Pharmacognosy (MUNI) Molecular and Cellular Interactions (UCA) Supervisors: Assoc. Prof. RNDr. Jan Hošek, Ph.D. (MUNI) Dr. Catherine Heurteaux, Director of Research CNRS (UCA) Thesis consultant: Dr. Nicolas Blondeau, Director of Research CNRS (UCA) Year: 2020 Number of Pages: 211 Keywords: stilbenes, inflammation, macasiamenene F, ischemia, neuroprotection Resumé Un grand pourcentage de troubles aigus et chroniques aux niveaux systémique et central s’accompagne d’une réponse inflammatoire excessive ou non résolutive du système immunitaire contribuant au développement de la maladie. L’accident vasculaire cérébral (AVC) ischémique est l’une des maladies les plus dévastatrices au monde où la neuroinflammation caractérisée par l’activation microgliale et la production de médiateurs pro-inflammatoires joue un rôle majeur dans la physiopathologie de l’AVC aggravant son issue. Cette thèse s’intéresse au potentiel anti-inflammatoire des stilbènes naturels et de leur capacité à intervenir dans l’activation médiée par le récepteur toll-like 4 (TLR4) des voies du facteur nucléaire-κB (NF-κB) et de la protéine activatrice-1 (AP-1). Plusieurs des 37 stilbènes testés ont montré la capacité : 1./ de réduire remarquablement l’expression des cytokines pro- inflammatoires, comme celui du facteur de nécrose tumorale α (TNF-α) et de l’interleukine- 1β (IL-1β), 2./ de diminuer l’activité NF-κB/AP-1, l’activation des protéines kinases activées par des mitogènes (MAPK) ainsi que la dégradation de l’inhibiteur κB-alpha (IκBα) dans les macrophages THP-1 et les monocytes THP-1-XblueTM-MD2-CD14. La première partie de cette thèse démontre un puissant effet anti-inflammatoire in vitro des stilbènes trouvés dans les plantes alimentaires et médicinales, résultat éventuellement applicable à la prévention des maladies inflammatoires systémiques. Simultanément, ce criblage pharmacologique a conduit à l’identification de composés au potentiel anti-inflammatoire le plus prometteur, parmi lesquels macasiamenene F (MF), stilbène prénylé très peu étudié de Macaranga siamensis. Le potentiel anti-inflammatoire de MF a ensuite été étudié au niveau du système nerveux central (SNC) sur le modèle de cellules BV-2 et de microglie primaire de souris stimulées par le lipopolysaccharide (LPS). MF a montré la capacité de réduire l’inflammation à n’importe quel stade du traitement. MF utilisé en prétraitement a radicalement réduit l’expression des gènes et des protéines du TNF-α et de l’IL-1β. De plus, MF a montré les effets cytoprotecteurs contre la mort de la microglie induite par le LPS. Lorsqu’il est appliqué en co- et post- traitement, MF a pu réduire l’inflammation, ce qui indique son utilité potentielle dans les troubles cérébraux aigus, tels que l’ischémie cérébrale. Par conséquent, la capacité de MF à contrecarrer d’autres mécanismes délétères de la cascade ischémique, tels que le stress oxydatif et l’excitotoxicité induite par le glutamate, a été ensuite étudiée. Bien que l’action antioxydante de MF ait été démontrée mineure, MF a exercé la capacité de protéger les neurones corticaux en cultures primaires contre les dommages excitotoxiques induits par le N- méthyl-D-aspartate (NMDA). Pour tester si MF pourrait antagoniser les conditions ischémiques délétères, les neurones corticaux traités par MF ont été exposés à une privation d’oxygène-glucose (OGD) de 1 h/2 h (modèle de l’OGD). Enfin, MF a été formulé dans des liposomes dans le but d’améliorer sa solubilité dans l’eau et de tester in vivo sur le modèle murin d’occlusion de l’artère cérébrale moyenne (MCAo). Mots-clefs : stilbènes, inflammation, macasiamenene F, ischémie, neuroprotection Abstract An enormous percentage of acute and chronic disorders at the systemic and central levels is underlined by an excessive or non-resolving inflammatory response of the immune system contributing to disease development. Ischemic stroke is undoubtedly one of the worst devastating disorders worldwide where neuroinflammation characterized by microglial activation and production of proinflammatory mediators plays a crucial role in stroke pathobiology worsening its outcome. This thesis deals with the anti-inflammatory potential of natural stilbenes and their ability to
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