Contribution to the Valorization of Plants Used in the Management of Rheumatic Diseases in Burkina Faso ()
1. Introduction
Rheumatism is a public health problem in developed countries. Sub-Saharan African countries are not concerned with because of priority diseases such as malaria, cardiovascular diseases and human immunodeficiency virus (HIV) infection. Over the last ten years, many studies have reversed this perception in low-income countries weakly affected by rheumatic diseases like rheumatoid arthritis (RA) [1]. For example, rheumatoid arthritis, which is chronic inflammatory and autoimmune rheumatism, had a world prevalence of 0.4% - 1% in 2015. In Burkina Faso, in-hospital frequency of 2.18% was reported by a study covering the period from 2006 to 2011 [2].
Rheumatism is a common chronic inflammatory disease, characterized by dysregulated inflammatory process in joint synovium that leads to the destruction of both cartilaginous and bones, resulting in pain, disability and destruction of articular structures. Complex autoimmune and inflammatory processes induce synovitis, swelling, and joint damage, after activation of components in both innate and adaptive immune systems. Rheumatism causes pain, weariness, and disability associated with a significant reduction in health-related, well-being and quality of life [3].
In community and economic fields, rheumatic diseases cause an invaluable loss of working time, greater than accidents, cardiovascular diseases and infections. The problem of Rheumatic-related disability is even pronounced in manual workers where entire musculoskeletal system is most solicited [4]. Repetition of painful crises and rheumatic disability compel patients to resort to both conventional, alternative or traditional medicine therapeutic care.
Therefore, more than 80% of the West African population resort to traditional medicine for treatment [5]. This therapeutic care is highly dependent on medicinal plants use and associated local knowledge [6] [7]. Cultural beliefs have a deep impact on choice of traditional medicine care by populations compared to economic reasons. Supply of health care and access to medicines is very weak or even non-existent and so expensive for African population. Moreover, despite the availability of generic drugs, many innovative treatments such as targeted therapy with monoclonal antibodies, remain inaccessible to low-income populations. Prices of conventional medicines range from two (2) dollars (anti-inflammatory drugs) to 100 dollars (targeted therapy) compared to traditional rarely exceed 1 dollar. Then, traditional medicine becomes a good alternative for health care coverage, especially in case of chronic pathology [5]. Hence, promoting traditional medicines and practices is encouraged by WHO and is included in public health policies in low-income countries. In Burkina Faso, out of 2067 species are listed and half have been registered with traditional uses including rheumatic diseases [2]. In a previous ethnobotanical survey, we reported that 73 species from 70 genera and 41 families are used by traditional health practitioners for rheumatism treatment in Ouagadougou, the political capital of Burkina Faso. The ten (10) most cited plants were selected for this study purpose which aims to provide factual evidences attesting their benefit in the treatment of rheumatism [2].
We then carried out a meta-analysis of the available scientific data pharmacologic properties of these plants in inflammatory joint pain relief. We also analyzed structural analogies between modern therapies compounds and plant metabolites to suggest qualitative structure-activity relation in pharmacological potential of these ten plants.
2. Material and Methods
2.1. Determination of Consensus Factors (FIC) and Fidelity Levels (FL) of Studied Plants
Determination of the informant consensus factor (FIC) and the fidelity level for identified plants was carried out online on 18 December 2018 according to method described by Hassan et al. [8]. We conducted a meta-analysis on the pharmacological properties of the 10 selected plants from December 2018 to September 2019.
Table 1 shows the different plant parts used in the treatment of rheumatic diseases, according to Youl et al. [2]. Research on scientific papers (26,595 articles) on plants has identified information on their chemical composition and pharmacological effects on rheumatic diseases (including joint pain).
2.1.1. Factor of Informant Consensus
The Informant Consensus Factor (FIC) represents independent variables that contribute to the agreement and consent in international scientific opinion. It was determined as previously described by Hassan et al. [8].
(1)
with: Nur, scientific articles related to the therapeutic use of the plant;
Nt, plant species and for calculations, Nt= 10.
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Table 1. Ten most used plants and parts for the management of rheumatic diseases.
Data were analyzed on Microsoft Excel 2013 and FIC values range from 0 to 1, where 1 indicates the highest level of consensus. The thresholds for this data analysis have been set at 5% (α = 0.05) which represent the probability of similar use in therapeutics claimed worldwide.
2.1.2. Fidelity Level
Fidelity Level (FL) represents the accuracy of the claimed medicinal use [9].
. (2)
with: X1, scientific articles combining plant and joint pain; X2, scientific articles combining plant and anti-inflammatory; X3, scientific articles combining plant and antirheumatic; Y, number of all citations for the name of the plant only.
Data was analyzed on Microsoft Excel 2013, and thresholds for data analysis have been set at 25% which represent the strength of fidelity showing that this indication is well recognized for this plant.
2.2. Study of Structural Analogies between Selected Plant Secondary Metabolites and Antirheumatics
Drugs used as antirheumatics for structural analogies study, include nonsteroidal anti-inflammatory drugs (salicylates, fecates, arylpropionic, arylacetic, oxicams, coxibs), anti-inflammatory steroids (Glucocorticoids), analgesics (morphine, paracetamol, metamizole), and antifouling agents (colchicine). First, basic chemical skeletons of these antirheumatic drugs were identified based on those of the three (03) major categories of secondary metabolites (phenolic compounds, nitrogen compounds and terpenic compounds). Secondly, documented chemical composition of plants allowed comparison with modern drugs basic chemical skeletons in order to identify potential structural analogies. The state of knowledge on these plants (pharmacological activity and chemical constituents) was carried out on scientific search engines such as PUBMED, Medline, EMBASE, Science Direct and Google scholar databases using keywords (plant names, joint pain, anti-inflammatory properties)
3. Results and Discussion
3.1. Determination of the Informant Consensus Factors and Fidelity Levels of Identified Plants
Review on scientific articles related to pharmacological activities of selected plants is presented in Table 2.
Zizyphusmauritiana Lam. was subject to the largest number of scientific publications (5610) while Trichiliaemetica Vahl had 644 publications. Anti-inflammatory use of these ten (10) plants retain an informant consensus factor up to 1. This suggests a scientific agreement and consent for anti-inflammatory properties of these plants. The ethno-medical and ethno-pharmacological evidence of these plants used for their anti-inflammatory properties could thus be confirmed by scientific publications analysis.
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Table 2. Informant consensus factors and fidelity levels on anti-inflammatory and antirheumatic properties of the ten (10) plants used by Health Tradipraticians in Ouagadougou.
Nur = articles related to the therapeutic use of plant, FIC = factors of informant consensus.
Estimation of fidelity level of use on inflammatory joint pain management showed 4 plants with more than 25% fidelity of claimed on inflammatory joint pain such as Trichiliaemetica Vahl (35.25%), Guierasenegalensis J.F.G.mel. (31%), Calotropisprocera (Ait) Ait.F. (28.29%) and Crescientiacujete L. (25.12%). Indeed, Trichilia emetica Vahl root powder mixed with potassium hydroxide and water traditionally cures inflammation [5]. Guierasenegalensis leaves extracts showed an analgesic effect and are widely used against rheumatism [7]. Calotropis species are used for the treatment of pain and rheumatism, like roots used against rheumatism, and latex and leaves used in the treatment of joint pain. So, several studies provide evidence of Calotropis species analgesic, anti-inflammatory and anti-nociceptive properties [10]. Crescientiacujete L. extracts exhibit anti-inflammatory activities [11] [12].
3.2. Study of Structural Analogies between Selected Plants Secondary Metabolites and Antirheumatics
Structural analogies between secondary metabolites found in selected plants and antirheumatic drugs are presented in Table 3 and Table 4. Illustration of chemical compounds found in medicinal plants showing similar basic chemical skeletons as anti-rheumatic drugs are provided in Figure 1.
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Table 3. Basic skeleton of phenolic derivatives found in antirheumatic drugs.
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Figure 1. Examples of selected plant secondary metabolites showing a basic chemical skeleton similar to antirheumatic drugs.
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Table 4. Basic skeleton corresponding to terpenic and nitrogen compounds found in antirheumatic drugs.
3.2.1. Basic Chemical Skeletons Corresponding to Phenolic Compounds
Analgesics and anti-inflammatories drugs used in the treatment of rheumatic pathologies presented a basic chemical skeleton like C6-C1, C6-C2 and C6-C3 type (Table 3), close to those of plant phenolic compounds [13]. Study of chemical compounds found in plants with the highest level of agreement for inflammatory joint pain care also indicates the presence of compounds showing similar basic skeletons C6-C1 and C6-C3 type.
1) C6-C1 Basic Chemical Skeleton Molecules
Trichiliaemetica Vahl contains C6-C1 phenolic acids such as gallic acid (1) (Figure 1) in the root bark [14]. Gallic acid shows anti-inflammatory properties by decrease expression and release of pro-inflammatory and inflammatory mediators, such as bradykinine, substance P, Cyclooxygenase 2 (COX-2), Nuclear Factor-kappa B (NF-κB), Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-5 (IL-5), Interferon gamma (IFN-γ) and Tumor Necrosis Factor α (TNF-α). It also inhibits polymorphonuclear agents involved in the inflammatory response and decreases the activity of myeloperoxidase (MPO) [15] [16]. Root also contains ferulic acid (2) (Figure 1) [17]. Ferulic acid showed promising anti-inflammatory activity (inhibition of TNF-α, Interleukin-6 (IL-6) and COX-2). Gallic acid, ferulic acid demonstrated inhibition of xanthine oxidase [14]. Guierasenegalensis J.F.G.mel contains nine galloylquinic acids, namely 3-O-, 5-O-, 1,3-di-O-, 3,4-di-O-,3,5-di-O-,4,5-di-O-,1,3,4-tri-O-,3,4,5-tri-O- and 1,3,4,5-tetra-O-galloylquinic isolated by column chromatography and HPLC from different plant parts. Among these nine (09) galloylquinic acids, 3,4,5-tri-O-galloylquinic is a new ethyl ester of polyphenol acid (3) (Figure 1). Gallic acid has also been isolated from leaves [18]. In addition, 3,4,5-tri-O-galloylquinic acid isolated from Guierasenegalensis J.F.G.mel. has showed to exhibit anti-HIV activity [19]. Phenols are present in leaves of Calotropisprocera (Ait) Ait.F. and in Crescientiacujete L. fruits [10]. It is recognized that phenolic compounds proceed in the same way as NSAIDs, and some of them inhibit other pro-inflammatory mediators [13].
2) C6-C3 Basic Chemical Skeleton Molecules
Guierasenegalensis J.F.G.mel. leaves extracts contain coumarin (4) and flavonoids such as quercetin (5) and rutin (6) (Figure 1) [19]. Trichiliaemetica Vahl root barks also contain flavonoids such as rutin (6) [20]. Calotropisprocera (Ait) Ait.F. leaves and barks contain flavonoids, mainly rutin (6) [20] which exhibit anti-inflammatory properties by reduction of the production of pro-inflammatory cytokines and inhibition of xanthine oxidase. In vivo, quercetin (5) has been shown to have anti-inflammatory properties by attenuating lipid peroxidation, platelet aggregation and capillary permeability. It also inhibits cyclooxygenases (COX), lipoxygenase (LOX) and lipopolysaccharide (LPS) which induces the production of TNF-α in macrophages and the production of IL-8 [21]. Crescientiacujete L. contains flavonoids in these fruits [22] which have anti-inflammatory properties [21].
3.2.2. Basic Chemical Skeletons Corresponding to Terpenic Compounds
Drugs used in inflammatory joint pain care present basic chemical skeletons close to steroid-like triterpene derivatives as corticosteroids and their derivatives (Table 4). Scientific publications indicate that many plant-derived triterpenes have anti-inflammatory properties [23].
Study of chemical compounds found in plants with the highest level of agreement for inflammatory joint pain care also indicates the presence of compounds showing similar basic skeletons of terpenoids. Steroid-like triterpene compounds have been identified in Trichiliaemetica Vahl [24], Guierasenegalensis J.F.G.mel. [25], Calotropisprocera (Ait) Ait.F. [26]. Similarly, limonoid type, a modified triterpenic compounds such as tetranortriterpenoids trichiline (7) (Figure 1) were found in the root bark of Trichiliaemetica Vahl [24] and saponoside type were found in Crescientiacujete L. fruits [22]. Limonoids showed a strong anti-inflammatory activity [23].
3.2.3. Basic Chemical Skeletons Corresponding to Nitrogen Compounds
Observations of chemical structures indicated that morphine and piroxicam have basic chemical skeletons of C6-C2-N type while colchicine would be of C6-C3-N type (Table 3) close to phenylalanine-derived compounds. Many alkaloids, especially the iso-quinoline alkaloids, exhibiting the same basic skeletons, are known to have anti-inflammatory and analgesic properties [27].
Study of chemical compounds found in plants with the highest level of agreement for inflammatory joint pain care also indicates the presence of nitrogen
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Figure 2. Examples of nitrogenous derivatives presenting anti-inflammatories properties found in selected plants used by tradipraticians and whose basic chemical skeleton differed from that of anti-rheumatic drugs.
compounds in three (03) plants in exception of Trichiliaemetica Vahl. Basic chemical skeletons of C6-C2-N and C6-C3-N type, similar to nitrogen compounds have not been identified in Guierasenegalensis J.F.G.mel. [18], Calotropisprocera (Ait) Ait.F. [10], and Crescientiacujete L. [11]. Nevertheless, we noted in Guierasenegalensis J. F. G. mel the presence of indolic alkaloids β-carboline type as harmalane, harmane and tetrahydroharmane (Figure 2) [28]. These compounds demonstrated anti-inflammatory activities by suppressing nitric oxide production and secretion of pro-inflammatory cytokines [29]. Similarly, nitrogen compounds like choline has been identified in the latex of the leaves of Calotropisprocera (Ait) Ait.F. Choline is a quaternary ammonium-like proto-alkaloid [30] that showed anti-inflammatory effects. We could not identify structural analogies between these nitrogen molecules, which potent anti-inflammatory properties have been already demonstrated and modern antirheumatics.
4. Conclusions
Determination of informing consensus factor and the fidelity level attest to the efficiency of selected plants for traditional care of joining pain and give evidence for a scientifically recognized worldwide. Study of structural analogies between plants compounds used in the treatment of inflammatory rheumatic diseases and modern drugs’ basic chemical skeleton indicates many similarities. Phenolic compounds C6-C1, C6-C3 type, similar to basic skeletons of anti-inflammatory and analgesic are found in selected plants. Then, steroid-like terpenic compounds with basic chemical skeleton close to corticosteroids have been identified in Trichilia emetica Vahl, Guiera senegalensis J.F.G.mel., Calotropis procera (Ait) Ait.F. These observations strengthen scientific basis for the use of Trichilia emetica Vahl, Guiera senegalensis J.F.G.mel., Calotropis procera (Ait) Ait.F. and Crescientia cujete L. in inflammatory joint pain treatment.
The subsequent evaluation of therapeutic equivalences will allow the development of plant-based phytomedicines, standardized in therapeutic equivalent of modern treatments per gram of dry plant material. Evaluation of QSAR of plant compounds as indolic alkaloids and modified triterpenic compounds with potent anti-inflammatory properties could give models for drug design and discovery in the area of new therapies development.