2. Use of C. arabicus in Traditional Medicine
Ensuring a sustainable supply of affordable medicines for the world’s fast-growing population (which now surpass 8 billion people) is a major challenge in today’s economy. The challenges are even broader for people with low resources living in rural areas. There is a major need to improve access to and the affordability of health care in rural communities
[11][12]. The World Health Organization (WHO) has estimated that about 80% of the world’s population use traditional medicine or rely on plant-based therapy for their primary care needs
[13]. Plants have long been used as traditional remedies to help fight human diseases and remain largely used today to combat parasitic and virus infections, cardiovascular, mental, and inflammatory diseases, cancers, and many other pathologies
[14][15]. Moreover, the demand for health-promoting products is increasing
[16]. Plants still represent a large untapped source of structurally novel compounds that might serve as a lead in the development of novel drugs
[17]. Many medicines of plant origin with analgesic and anti-nociceptive activity have been used for a long time without any major adverse effects
[18][19]. Similarly, traditional herbal medicines and natural plant products contribute considerably to the treatment of cancers
[20][21]. The bioprospection of medicinal plants remains a valid approach to identify new molecules which could be active against cancer and inflammatory diseases
[22][23][24].
The use of
C. arabicus in traditional medicine is not largely documented, with only sparse citations in scientific reviews. The plant is known in Morocco for the treatment of diabetes
[25]. Apparently, an infusion prepared from the flower heads of the plant, drunk twice a day, could be useful to combat type 2 diabetes
[26][27] (
Figure 2).
C. arabicus can be used alone or combined with other plants, such as
Rubia peregrina,
Corrigiola telephiifolia, or
Ridolfia segetum, to prepare an antidiabetic decoction
[28]. There are other reports primarily citing the use of the species
C. mixtus (L.) Chevall
[29] and
C. scariosus (
Ball) Oberpr. and Vogt
[30], but not
C. arabicus, for the treatment of diabetes. Other anti-diabetic Moroccan Asteraceae are cited also
[31][32] and could be combined with
C. arabicus. Beyond diabetes, the uses of
C. arabicus for the treatment of digestive disorders, neurological troubles, and respiratory and urogenital affections have been mentioned, without much detail
[33]. Apparently, the plant is “good for stomach and anemia” but robust experimental evidence to support these claims is lacking
[7].
Figure 2. The uses of C. arabicus in traditional medicine. Decoctions prepared from flowers heads are used to treat diabetes and total extracts are used to combat a variety of diseases. Essential oils from the leaves and stems provide remedies to treat microbial infections.
3. Pharmacological Activities of C. arabicus Extracts
Essential oils (EO) extracted from the aerial parts of
C. arabicus have revealed the marked antimicrobial activities associated with a rich monoterpenic compounds content (
Figure 2). In particular, an essential oil derived from the plant stems and leaves showed antibacterial activities against the opportunistic human pathogen
Bacillus cereus and
Enterococcus faecalis which is at the origin of nosocomial infections, but it showed no effect against the hard-to-treat pathogen
Pseudomonas aeruginosa. This leaf/stem-derived EO principally contained the monoterpenes sabinene (13%), α-pinene (8%), β-pinene (12%), myrcene (7%), and many other volatile terpenes in smaller proportions (36 monoterpenes were identified) (
Figure 3).
Figure 3. Structures of various natural products identified from essential oils or alcoholic extracts of Cladanthus arabicus.
An EO prepared under identical conditions from the plant’s flowers revealed a much poorer monoterpenes content, essentially only sabinene (23%) and β-pinene (32%)
[34]. The composition of the essential oil can vary significantly from one study to another, depending on the process, the plant origin and its growth, or the collecting season. For example, an EO made from
C. arabicus’ aerial parts was found to contain up to 60 terpenic compounds, principally sabinene (31%), β-pinene (17%), myrcene (12%) and α-pinene (5%). In this case, the EO was characterized for its strong antioxidant activity (IC
50 = 55.4 μg/mL in a DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay) and its antimicrobial effects, notably against
Micrococcus luteus bacterium and the pathogenic fungus
Candida albicans (MIC = 0.187 mg/mL in both cases)
[35]. In a subsequent study, the same authors further tested this EO against other microbes and found activities against
Escherichia coli (strain ATCC 25922),
Klebsiella pneumoniae (strain S12b/16), and
Enterobacter cloacae (strain S5/16), but at significantly higher doses than were measured for reference antibiotics such as amoxicillin and neomycin. Interestingly, the EO showed a synergistic activity with amoxicillin against
Proteus mirabilis (strain S32/16), a Gram-negative bacterium that is frequently implicated in urinary tract infections
[36]. The potent antibacterial activity of
C. arabicus EO and its strong interaction with amoxicillin warrant further investigation. Apparently, the terpene content of
C. arabicus EO is quite variable from one preparation to another. Recently, Mziouid and coworkers
[37] reported the antioxidant activity of an EO from
C. arabicus which contained α-pinene (5.7%) and β-pinene (23.6%), but also a large proportion of tau-cadinol (9.5%) (
Figure 3), a sesquiterpene commonly found in EOs but not mentioned in the aforementioned preparations using
C. arabicus. T-cadinol is known to be an anti-trypanosomal agent which is able to induce a mitochondrial impairment in
Trypanosoma cruzi parasites responsible for the Chagas disease
[38]. The
C. arabicus EO also contained diethyl phthalate (DEP, 7.9%) which is an unwanted estrogenic endocrine-disrupting chemical (
Figure 3). In this case, the EO exhibited a modest antioxidant activity (IC
50 = 1.33 mg/mL in the DPPH assay)
[37]. A well-established, robust process is needed to prepare an EO in a reproducible manner with a constant, stable composition, which is free from toxic chemicals (following the recommendations of the European Pharmacopoeia, for example).
The antioxidant activity is more pronounced when a total plant extract is used instead of an EO. For example, the antioxidant IC
50 value dropped from 1.33 mg/mL to 0.23 mg/mL when a methanolic extract was used in place of the EO from
C. arabicus, due to the high phenolic content of the extract
[37]. A phytochemical analysis of an alcoholic extract of the aerial parts of
C. arabicus has revealed the presence of two major components, caffeic acid (4.9 mg/kg) and protocatechuic acid (4.7 mg/kg), followed with other polyphenols such as ferulic acid (1.8 mg/kg), 4-hydroxybenzoic acid (1.5 mg/kg), vanillin, and vanillic acid (both 1.6 mg/kg), plus a series of minor components including flavonoids which are sometimes glycosylated (diosmetin, luteolin, apigenin-7-glucoside) (
Figure 3). The high polyphenols content, notably caffeic acid, suggests a possible use of the plant in combatting adverse hematologic events such as thrombocytopenia
[39]. Caffeic acid is a strong antioxidant and an anti-inflammatory agent with cardioprotective and hepatoprotective effects. This common natural product is considered to be beneficial in limiting the progression of diabetes mellitus and its associated complications
[40]. Protocatechuic acid is also a chemoprotective agent which is notably able to protect cardiomyocytes from oxidative damages
[41]. These two polyphenols are commonly found in fruits, vegetables, grains, and herbal medicine; thus, they are definitely not specific to
C. arabicus. Nevertheless, these compounds are important. Polyphenols from Mediterranean plants have benefits in the prevention and treatment of various diseases, notably skin diseases such as atopic dermatitis, psoriasis, and chronic urticaria
[42].
In
C. arabicus extracts, the polyphenol content was rich, whereas the levels of heavy metals (Cd, As and Pb) were low, and the extract revealed a marked antibacterial activity against
Escherichia coli strain S33/16 (MIC = 0.125 mg/mL)
[43]. The same hydro-methanolic extract has revealed the presence of diverse flavonoids and phenolic acids, including isochlorogenic acid and cinnamic acid (
Figure 3). All together, these compounds are responsible for the marked antioxidant activity of the extract, as well as its modest inhibitory activity toward cholinesterase, acetylcholinesterase, tyrosinase, and α-glucosidase enzymes
[44].