Back to plants for drug discovery: from ethnomedicine to more conventional approaches

Over the last years, there is rekindling of interest in drug discovery from botanical resources. This thesis proposed two different approaches (from ethnomedicine to scholarly strategies) for drug discovery from medicinal plants, identifying the areas of knowledge involved and addressing the challenges encountered, with the aim of enhancing the chance of success of the overarching process. The first approach consists to review the literature to increase understanding of a plant of interest and generate strong hypotheses for future drug development research on this plant. Illustrating such an approach, we focused on Tithonia diversifolia (Hemsl.) A. Gray (TD). Knowledge about TD was collected from both online databases and non-electronic resources. Overall, a total of 1,804 reports have been collected. After subsequent duplicates removal and screening for relevant titles and abstracts, a total of 119 text articles were obtained and assessed for eligibility. Finally, 168 articles were selected, of which forty-nine were added after analyses of the reference lists of the included papers. We found that all parts of the plant are valued in several cultures for a wide scope of ailments ranging from topical issues —wounds, skeleto-muscular disorders, abscesses, dermatological conditions, and stomach pains— to systemic disorders such as diabetes, malaria, fever, hepatitis and infectious diseases. Importantly, most of the ethnomedical claims of TD have been substantiated in several studies conducted in vitro and in vivo in animals. Sometimes, findings were conflicting and thanks to this review, we were able to assess the weight of evidence for each pharmacological effect of TD. The anti-inflammatory, antimalarial, antidiabetic, antioxidant and anticancer effects do stand out but there is also a stunning array of other relevant pharmacological effects. Chemically, a hundred of chemicals, mainly terpenoids and phenols, have been isolated from various TD extracts so far. Of these, some compounds including Tagitinin C have been linked to the pharmacology of TD. About the toxicological profile, we were able to conclude based on evidence that short-term oral administration of TD is relatively well-tolerated in animals when taken at doses less than 100 mg/kg. The second approach consists to screen the ethnomedical knowledge of indigenous people to select the best plant candidate to launch a drug discovery campaign. So, we carried out a 6-month cross-sectional questionnaire-based survey to explore the use of medicinal plants (MP) in People living with HIV (PLHIV) in the city of Dschang (West Region, Cameroon). Of the 247 HIV-infected respondents, 54.9% reported to use plants. MP users were then kindly invited to provide photographs and/or specimens of plants for botanical identification. A total of 70 MP, chiefly the herbs, were mentioned by informants (82.2% of total MP users, mean±SEM: 2.2±0.2 MP/subject, min 1, max 11), of which forty-nine have been botanically identified. Commonly reported pathological conditions or symptoms treated with MP included malaria (n = 27, 18.4% of total citations), cough (n = 20, 13.6%) and abdominal pain (n = 16, 10.9%). The benefits of using MP reportedly ranged from moderate (n = 60, 57.7%) to complete (n = 35, 33.7%) relief, while only 8 subjects (7.7% of MP users) reported no change in their terms. Interestingly, 2 subjects (33.3 % of respondents) denounced fatigue and weight loss. We also observed that THPs were the main advisors of PLHIV on the use of MP. Thus, in the rest of our study, their knowledge and attitudes towards HIV/AIDS were surveyed aiming at understanding whether they may be an appropriate resource to assist in the scaling up of HIV prevention and treatment delivery services in Cameroon. 16 THPs were recruited by the chairperson of the Cooperative Society of Producers of Medicinal Plants of West Region based on their good reputation in traditional healing practice. Three of them acknowledged the use of MP to manage HIV diseases in their clients. All THPs who agreed to participate in the survey were also evaluated for their knowledge of HIV transmission, prevention and diagnosis. We found that their knowledge related to HIV was relatively low raising concern about their aptitude to effectively assist conventional health practitioners in fighting against HIV/AIDS. Resulting from literature mining and ethnomedical claims is the adoption of a relevant pharmacological testing system. In any case, the testing systems should represent the biological activities that best match the ethnomedical uses of the selected plant species. In addition, it is important to bear in mind that plant extracts are complex mixtures containing various components and, therefore, their overall activity results from interactions between their naturally occurring ingredients. It is with this background that we conducted a study of comparison of the effects of a whole extract of a particular strain of Cannabis sativa L. to that of cannabidiol (CBD). We knew cannabis is endowed with a potent anti-inflammatory effect attributable mainly to CBD, but also to its entourage. This mechanism by which other compounds occurring in cannabis may contribute to its clinical effects has been espoused as an “entourage effect”. The concept of entourage effect was first introduced in 1998 by Ben-Shabat and Raphael Mechoulam but still, there was no hard evidence that the entourage effect is real. So, thanks to a collaboration with a pharmaceutical company, we grew a particular strain of cannabis deprived of THC and standardized in 5% CBD (CM5). Then, we tested the effects of an extract of CM5 in parallel to that of pure CBD at equimolar concentrations on neutrophil functions including oxidative metabolism, migration and production of proinflammatory cytokines. Results show that CM5 0.05-50 μg/mL and CBD 10-8-10-5 M inhibit the neutrophil functions including ROS production, cell migration, mRNA levels of proinflammatory cytokines (but at the protein level, only TNF-a was inhibited) to a comparable extent, indicating that CBD may be the main responsible of the anti-inflammatory effects of Cannabis. The effects of CBD and CM5 show however remarkable differences in terms of potency and efficacy, suggesting that beyond CBD, other components of cannabis may contribute to its biological effects. As a whole, such results support the use of cannabis and CBD to stem inflammation, however also warrant in-depth investigation of the underlying cellular and molecular mechanisms to better exploit their therapeutic potential.