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Le Cannabis Thérapeutique, Application À La Maladie De Parkinson Et Essai De Mise En Forme Galénique Jérémie Demontoux

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Le Cannabis Thérapeutique, Application À La Maladie De Parkinson Et Essai De Mise En Forme Galénique Jérémie Demontoux Le cannabis thérapeutique, application à la maladie de Parkinson et essai de mise en forme galénique Jérémie Demontoux To cite this version: Jérémie Demontoux. Le cannabis thérapeutique, application à la maladie de Parkinson et essai de mise en forme galénique. Sciences pharmaceutiques. 2016. dumas-01267037 HAL Id: dumas-01267037 https://dumas.ccsd.cnrs.fr/dumas-01267037 Submitted on 3 Feb 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITE DE BORDEAUX COLLEGE SCIENCES DE LA SANTE U.F.R. DES SCIENCES PHARMACEUTIQUES Année 2016 Thèse n°24 Thèse pour l’obtention du DIPLOME D’ETAT DE DOCTEUR EN PHARMACIE Présentée et soutenue publiquement Le 12 janvier 2016 Par Jérémie DEMONTOUX Né le 22 octobre 1987 à Sainte-Clotilde LE CANNABIS THERAPEUTIQUE APPLICATION A LA MALADIE DE PARKINSON ET ESSAI DE MISE EN FORME GALENIQUE Directeur de thèse Madame Catherine CHEZE Jury Madame Catherine CHEZE Maître de conférences Président Monsieur Michel GUYOT Maître de conférences Assesseur Monsieur Jean-Pierre Vacher Docteur en pharmacie Assesseur 1 Remerciements A Madame Catherine Chèze, D’avoir accepté d’encadrer mon travail et de me faire l’honneur d’être ma présidente de jury. Je vous remercie d’être présente aujourd’hui et vous adresse mes plus sincères remerciements. A Monsieur Michel Guyot De me faire l’honneur de juger ma thèse et de vous être rendu disponible. A Monsieur Vacher Jean-Pierre Pour votre participation en tant que jury et pour m’avoir accueilli au sein de votre pharmacie durant tout mon cursus universitaire. Merci de m’avoir accordé votre confiance et pour toutes les connaissances que vous m’avez apporté. A mes parents Qui m’ont toujours soutenu dans mes études et mes projets. A Ambre, Angeline, Elodie, Henri et Marion Pour votre collaboration et votre aide précieuse. 2 Liste des abréviations 2-AG: 2-arachidonyl glycérol 2-AG éther: 2-arachidonylglycérol éther AADC: Amino-acid décarboxylase AC : Adénylate cyclase ACEA : Arachidonyl-2'-chloroethylamide ADNc : Acide désoxyribonucléique complémentaire AEA: Anandamide AFSSAPS : Agence française de sécurité sanitaire et des produits de santé AjA : Acide ajulémique AMM : Autorisation de mise sur le marché AMPc: Adénosine mono phosphate cyclique ARNm : Acide ribonucléique messager ATU : Autorisation temporaire d’utilisation CBC: Cannabichromène CBD: Cannabidiol CBDV: Cannabidivarine CBG: Cannabigerol CBN: Cannabinol CEPS : Comité économique des produits de santé COMT: catéchol-O-méthyltransférase DAG: Diacylglycérol DARPP-32: Dopamine and cAMP-regulated phosphoprotein DDC: dopa-décarboxylase EMA: European Medicines Agency ERK: Extracellular signal-related protein kinase FAAH: Fatty acid amine hydrolase FDA: Food and Drug Administration FSH: Hormone folliculostimulante GLP-1: Glucagon-like peptide 1 IgE: Immunoglobuline de type E IL-8: Interleukine-8 IP3: Inositol tri-phosphate JNK: Jun kinase LH: Hormone lutéinisante LPI: lysophosphatidylinositol MAGL: Monoacylglycerol lipase MAO-B: Monoamine oxydase de type B MAP: Mitogen activated protein 3 MCP: Monocyte chemoattractant protein MOG : Myelin oligodendrocyte glycoprotein NADA: N-arachidonyl dopamine NA dopamine: N-arachidonyl dopamine NAEs: N-acyl-ethanolamines NAd: Noradrénaline NA tyrosine: N-arachidonyl tyrosine NFAT: the nuclear factor of activated T cells NFkB: Nuclear factor kB NGF: Nerve growth factor Nhe: Na+/H+ exchanger NRS: Numeral Rating Scale OAE : O-arachidonyl éthanolamine PA : Acide phosphatidique PCR : Polymerase chain reaction PE : Phosphatidyléthanolamine PI: Phosphoinositides PI-PLC : phospholipase C sélective pour les phosphoinositides PI3K: Phosphoinositide 3-kinase PKA: Protéine kinase A PLA2 : Phospholipase A2 PLC : Phospholipase C PLD: phospholipase D PPAR : Récepteur activé par les proliférateurs de peroxysomes PRGC : Peptide relié au gène de la calcitonine PTZ : Pentylènetétrazole RCPG : Récepteur couplé aux protéines G SIDA : Syndrome d’immunodéficience active SNC : Système nerveux central Syk: Spleen tyrosine kinase TH: Tyrosine hydroxylase THC: Tetrahydrocannabinol THCV: Tétrahydrocannabivarine TMZ: Temozolomide TNF: Tumor necrosis factor TNFα: Tumor necrosis factor α TRPV: Transient receptor potential vanilloid 4 Table des matières REMERCIEMENTS…………………………………………………………………………………………………………………………………………..2 LISTE DES ABREVIATIONS…………………………………………………………………………….………………………………………………..3 INTRODUCTION……………………………………………………………………………………………………………………………….…………….8 PARTIE UNE : CANNABINOIDES ET SYSTEME CANNABINOIDE…………………………………………………………………….…10 I) LES CANNABINOÏDES ............................................................................................................................... 10 A) LES ENDOCANNABINOÏDES ........................................................................................................................... 10 1) L’anandamide .................................................................................................................................. 10 2) Le 2-arachidonylglycérol (2-AG) ....................................................................................................... 13 3) Les voies de dégradation de l’anandamide et du 2-arachidonylglycérol[6] ....................................... 16 4) Le 2-arachidonylglycérol éther ......................................................................................................... 20 5) Le N-arachidonyl dopamine ou NADA ............................................................................................... 21 6) La virodhamine ................................................................................................................................ 24 7) Le lysophosphatidylinositol............................................................................................................... 25 B) LES CANNABINOÏDES NATURELS .................................................................................................................... 26 1) Le delta-9-tétrahydrocannabinol ...................................................................................................... 26 2) Le delta-8-tétrahydrocannabinol ...................................................................................................... 27 3) Le cannabinol ................................................................................................................................... 27 4) Le cannabidiol .................................................................................................................................. 28 5) Le cannabigérol ................................................................................................................................ 28 6) Le cannabichromène ........................................................................................................................ 29 7) La tétrahydrocannabivarine ............................................................................................................. 30 C) LES CANNABINOÏDES DE SYNTHESE ................................................................................................................. 31 1) Les cannabinoïdes de synthèse utilisés dans la recherche ................................................................. 32 2) Les cannabinoïdes de synthèse utilisés à des fins médicales ............................................................. 33 II) LES RECEPTEURS AUX CANNABINOÏDES .................................................................................................. 41 A) LE RECEPTEUR CB1 .................................................................................................................................... 41 1) Structure et découverte .................................................................................................................... 41 2) Localisation [100] ............................................................................................................................. 41 B) LE RECEPTEUR CB2 .................................................................................................................................... 42 1) Structure et découverte .................................................................................................................... 42 2) Localisation ...................................................................................................................................... 43 C) LA MISE EN EVIDENCE D’UNE COLOCALISATION ENTRE LES RECEPTEURS OPIOÏDES ET LES RECEPTEURS AUX CANNABINOÏDES . 44 D) COUPLAGE ET SIGNALISATION DES RECEPTEURS CB1 ET CB2 [101], [105] .............................................................. 45 1) Les principales voies de signalisation (figure 27) ............................................................................... 45 2) La sélectivité de réponse des récepteurs aux cannabinoïdes ............................................................. 47 E) LE RECEPTEUR TRPV1 ..............................................................................................................................
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