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Modulation of the NLRP3 Inflammasome Activity by Traditional Medicines Used to Treat Asthma in Rwanda

par Tomani, Jean
Président du jury Vanhamme, Luc
Promoteur Souopgui, Jacob
Co-Promoteur Muganga, Raymond
Publication Non publié, 2021-06-23

Thèse de doctorat

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Résumé :

Inflammasomes are cytosolic protein platforms whose assembly/activation, in order to resolve various types of threats, can be triggered by a multitude of microbial and host derived stimuli. Their discovery was the key breakthrough in the understanding of inflammation initiation. Although beneficial in clearing microbes and restoring physiological or tissue homeostasis, aberrant or excessive stimulation of inflammasomes leads to various pathologies. The activation of NLRP3 inflammasome is associated with the physio-pathogenesis or the potentiation of the severity of so many diseases including respiratory diseases, such as asthma, COPD, COVID-19, malaria, diabetes, atherosclerosis, etc. Considering the extent of the NLRP3 inflammasome in diseases, therapies targeting the inhibition of its activation appear as a promising approach for the management of a wide range of diseases. The objective of this research work was to investigate the potential of Rwandan medicinal plants in the inhibition of the NLRP3 inflammasome. To this end, we first carried out a field survey to collect ethnobotanical information on plants used for the treatment of asthma in Rwanda. The present thesis is divided into two main parts:- The ethnobotanical study and screening of Rwandan medicinal plants with inhibitory activity on NLRP3 inflammasome activation;- The isolation and structure characterization of the active ingredients responsible for NLRP3 inflammasome inhibition, and the investigation of antiplasmodial activity of selected plants.In the first part, 19 herbal recipes were reconstituted from 61 medicinal plants based on an ethnobotanical survey. Most of these recipes exhibited significant inhibition of the NLRP3 inflammasome activation. The four recipe extracts named R03Cn and R07Kn aqueous extracts, and R10MK and R19Sz organic extracts significantly downregulated the activation of caspase-1 (more than 70% at 50 µg/ml). As R19Sz revealed the best NLRP3 inflammasome inhibitory activity and was less toxic it was hence selected for further investigations. In the second part of the work, two unstudied plants from the R19Sz recipe were submitted to a bio-guided fractionation. This led to the isolation and identification of compounds including caffeic acid, isoquercetin, kaemferol-3-O-galactoside as being the major constituents responsible for the inhibition of NLRP3 inflammasome activation in H. noldeae, and to the isolation and identification of 7-O-glucopyranosyl-isoprunetin, isoprunetin, and luteolin as the main compounds responsible for the inhibitory activity of NLRP3 inflammasome activation in E. montanum. Additionally, in vitro anti-plasmodial activities coupled to cytotoxicity assays of some bio-guided fractionation of E. montanum led to the isolation and determined antiplasmodial activity of Eucomic acid (IC50 = 0.057µg/ml), 7-O-glucopyranosyl-isoprunetin (IC50 = 0.113 µg/ml), isoprunetin (IC50 = 0.042 µg/ml), Isoluteolin (IC50: 0.121 µg/ml) as the main compounds responsible for the antiplasmodial activity with the high selectivity indexes of 6 577, 2646.7; 5264.3 and 2005.8, respectively .Overall, the present work has potentiated the role of Rwandan herbal medicines in the treatment of asthma and malaria while paving ways at the molecular and functional levels allowing to say that these plants likely act on inflammation by inhibiting the NLRP3 inflammasome activation.