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2021-06-11 - Travail avec promoteur/Doctorat - Anglais - 291 page(s)

Aro Rania , "Pathogenesis of essential tremor: characterization of potentially involved endogenous alkaloids of dietary origin and evaluation of their activity on an original 3d neurosphere model", Duez Pierre (p) , Manto Mario , soutenue le 2021-06-11

  • Codes CREF : Chimie analytique (DI1314), Neuropathologie (DI332C), Pharmacognosie (DI3410), Sciences pharmaceutiques (DI3400), Toxicologie pharmaceutique (DI3440), Chimie des denrées alimentaires (DI3825)
  • Unités de recherche UMONS : Neurosciences (M119), Chimie thérapeutique et Pharmacognosie (M136)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
Texte intégral :

Abstract(s) :

(Anglais) Objectives Our work aimed to (i) study, thanks to an original analytical approach, the formation of β-carbolines alkaloids and isoquinolines, from volatile and non-volatile carbonyl compounds generated by the Maillard reaction; and (ii) identify their possible implication in the pathogenesis of essential tremor. Methods The literature suggesting a link between meat overcooking, β-carbolines and essential tremor etiology, we began by exploring the levels of β-carbolines alkaloids in overcooked meats to assess whether the actual levels are as low as described (3,8 - 8.5 ng/g). In view of the difficulties and the dubious interest in measuring β-carbolines in meat, at levels hardly accessible to the analytical equipment available in our laboratory, we decided to focus our attention on cooking compounds that could be involved in the generation of biologically active endogenous alkaloid artefacts. Thus, we developed a methodology to search for precursor carbonyl compounds produced during the Maillard reaction in overcooked meats to (i) extract and identify volatile and non-volatile carbonyls; (ii) study their reactivity with endogenous amines (spontaneous reactions at 37°C) and identify the reaction products; (iii) study in silico their predicted pharmacokinetic and toxicological properties towards the central nervous system; (iv) study in vitro their possible toxicity on a 3D neurosphere model; (v) test their possible tremorgenic involvement in an in vivo model. Results and conclusion This approach allowed us to identify the spontaneous synthesis of the alkaloid 1-benzyl-6,7-dihydroxy-1,2,3,4 tetrahydroisoquinoline (1-benz-THIQ-diol), likely to be endogenously formed, that in silico predicted possible CNS toxicant effect to propose a pharmacological study to reveal a possible relation with ET. To assess the neurotoxicity of harmane and 1-benz-6,7-diol THIQ, we have developed a 3D neurosphere culture (implemented for the first time at UMONS). This culture has shown its ability to yield a reproducible 3D model in terms of diameter, morphology and proportions of cells present (neurons / astrocytes); this is moreover an interesting model for toxicity studies. The role of harmane as a neurotoxic agent was supported in this study, but at a high concentration hardly compatible with its content in overcooked meat. So far, our in vitro data do not support an eventual neurotoxic effect for 1-benz-6,7-diol THIQ. We applied this last compound, which has not been studied in the literature, to an animal model of essential tremor for a preliminary study that remains to be pursued (tests carried out at the University of Bristol, in collaboration with Dr Kathryn Bennett).