Traditional uses , phytochemistry and biological activities of Cotula cinerea Del : A review

Cotula cinerea Del. belongs to the family Asteraceae. It is widely used in the traditional medicinal system for the treatment of various ailments such as colic, cough, diarrhea, digestive disorders, rheumatism, urinary and pulmonary infections, fever and headaches. Cotula cinerea contains a wide range of phytochemical compounds such as saponins, essential oils, tannins, flavonoids, steroids, and terpenoids. This paper reviews information pertaining its traditional uses, phytochemistry and biological activities such as antibacterial, antifungal, antioxidant, herbicidal, anti-diarrheal and analgesic properties. It is hoped that the information presented here might stimulate further studies that will possibly lead to development of therapeutic agents from this plant.


INTRODUCTION
Herbs are largely used in ethnomedicine in the form of traditional preparations or derivatives of their pure active ingredients [1].Medicinal plants represent natural sources of agents that can be used for the treatment of several diseases [2].According to the World Health Organization (WHO), a large percentage of the people in developing countries depends mostly on medicinal plants for basic healthcare needs [3].Medicinal plants have played a central role in the drug discovery process, due to their richness in bioactive natural products [4].Indeed, several classes of bioactive compounds such as saponins, phenolics, lignans, glycosides, flavonoids, terpenes, and alkaloids have been used in the modern drug system, due to their potent therapeutic properties [5,6].
However, some information on plants used in traditional medicine are not readily available to the scientific community because they are presented in the language of the local population, and so are limited in circulation to those localities [7].Many researchers have discussed the possibility of integrating traditional medicine into the public health system [8].This requires collection, organization and wide publication of all information about traditional medicine.
Cotula cinerea is one of the most used plants in traditional medicine in the northern Sahara of Algeria and in Morocco.The present review highlights the phytochemistry, and the various traditional uses and pharmacological properties of C. cinerea.

CLASSIFICATION OF C. CINEREA
The classification and vernacular names of C. cinerea are given in Table 1.Cotula cinerea is a small annual plant (5 to 15cm in height) with a woolly appearance.It rarely reaches a height of 40cm and is characterized by a whitish-green stem, diffuse or erect and covered with small dense hairs.The leaves are small, whitish-green in color and covered with small, dense hairs (Figure 1).In addition, the leaves are entire, thick and velvety, and are cut into three to seven teeth (or fingers), resembling slightly closed hands [9,13,14].The flowers are yellow and grouped into discoid hemispherical heads (6 to 10mm in diameter) at the tip of a short stem (Figure 2).The fruits of this species are small achenes, each of which does not exceed 5mm in diameter [14].
[30] a: sample harvested at flowering period; b: sample harvested at the fruiting period.Results from analysis and identification of components showed that the main constituents of essential oil from the aerial parts of C. cinerea vary from region to region.The structures of some major compounds are given in Figure 4.The qualitative and quantitative differences in the chemical compositions of essential oil could be attributed to several factors.The chemical components of essential oils are influenced by several intrinsic and extrinsic factors [42].
Qualitative variation in oil composition is thought to be influenced by intrinsic genetic factors, whereas quantitative variation is influenced by extrinsic factors [43].It has been revealed that the composition of the essential oils is influenced by a multiplicity of factors such as plant ontogeny, site of oil production, photosynthesis, plant growth regulators, plant density, soil salinity, harvesting stage, seasonal variations and climatic conditions [44].

PHARMACOLOGICAL ACTIVITIES OF C. CINEREA
Several pharmacological activities and medicinal applications of C. cinerea are widely known.A summary of the biological studies on this plant is presented below.

Antibacterial activity of C. cinerea
The  [47].Flavonoid and cell wall polysaccharide (hemicellulose and methylated pectins) extracts of the leaves and flowers of C. cinerea inhibited mycelia growth, germination and sporulation of the pathogenic fungi Fusarium oxysporum f.sp.albedinis [16].In the same study, flavonoid extracts reduced the relative virulence, and inhibited the cellulase activity of the fungi.However, the synthesis of Fusarium oxysporum toxins was not affected.
It is important to point out that the antimicrobial effects of the major identified constituents of the essential oils from C. cinerea were not investigated in previous studies.
Many studies have demonstrated that the inhibitory effect of an essential oil results from a complex interactions between its different constituents: these interactions may produce synergistic, additive or antagonistic effects even with components present at low concentrations [48,49].
In another study, the antioxidant activity of the essential oil of C. cinerea collected from South Morocco was stablished using DPPH free radical-scavenging, ß-carotene/linoleic acid bleaching, and ABTS free radical scavenging assays [50].

In vivo anti-diarrheal effect of C. cinerea
Diarrhea is one of the most common causes of morbidity and mortality in many countries.In third world countries, it is responsible for the death of millions of people each year.Children are more susceptible to this disease which is considered as the second leading causes to death of children less than five years old [51].Traditionally, C. cinerea plays an important role in the treatment of diarrhea and gastrointestinal disorders.However, there is limited scientific evidence supporting the use of this plant as an antidiarrheal agent.Aqueous extract of the aerial-part of C. cinerea (collected during the flowering period from the Errachidia Sahara region in Morocco) was tested for antidiarrheal activity using castor oil-induced diarrhea rat model, and also for gastrointestinal transit in mice [52].The results showed that oral administration of the aqueous extract at doses of 50, 100 and 250 mg/kg significantly reduced fecal output of the rats by 30.17, 56.79 and 100 %, respectively, and increased the time taken to reach 100 mg/kg, while the reduction in fecal output by loperamide (10 mg/kg), was 100 % when compared with the untreated group.The results of gastrointestinal motility test revealed that small intestinal motility of charcoal meal in mice was significantly inhibited (48.57%) at 250 mg/kg of the aqueous extract when compared to the control, while the inhibition produced by loperamide (10 mg/kg) was 78.5 %.The authors suggested that the antidiarrheal effect of the aqueous extract was probably exerted through an anti-secretory mechanism and/or antispasmodic effect which reduced intestinal contractions thereby allowing a greater time for absorption of water.
These results lend some credence to the widespread traditional use of C. cinerea as an antidiarrheal agent by the Northern Africa population.

Herbicidal effect of C. cinerea
The herbicidal activity of C. cinerea against Melilotus indicus (potential seed crop contaminant causing great loss in crop productivity) has been investigated [25].The results showed that percentage germination, plumule and radicle lengths, and seedling dry weight were significantly inhibited by applying different concentrations of C. cinerea shoot extract.The authors also evaluated the effect of C. cinerea shoot powder mixed with different levels of sandy loam soils (on weight-to-weight basis), on some growth parameters, total available carbohydrates and total protein contents of M. indicus.It was revealed that the shoot and root lengths of M. indicus were significantly affected by different levels of C. cinerea shoot powder.The leaf area index and the total photosynthetic pigments were significant reduced in the recipient species by treatment with different levels C. cinerea shoot powder.On the other hand, carotenoid content was significantly increased with increase in C. cinerea shoot powder level.Total available carbohydrates and total protein contents of the recipient species were significantly decreased with increase in the amount of C. cinerea shoot powder.
Based on these results, there is a possibility of using the allelopathic potential of C. cinerea directly or in structure leads, for the discovery and development of environmental herbicides.

Analgesic properties of C. cinerea
Studies have been carried out on the possible analgesic effects of different extracts of C. cinerea (collected from Zagora, Morocco) [46].Ethyl ether, ethyl acetate or n-butanol, and the reference drug acetyl salicylic acid, were orally administered to mice at a dose of 100 mg/kg, while mice in the control group received only water.After 1 h, 0.6 % acetic acid solution was injected intraperitoneally to the mice at a dose of 15 mL/kg.Nociception was evaluated 15 min after acetic acid injection by counting the number of abdominal constrictions for a period of 5 min.The results showed moderate analgesic effects of the ethyl acetate and n-butanol extracts, with constriction inhibitions of 50 and 40.21 %, respectively.In contrast, the constriction inhibition produced by the ethyl ether extract (62.49%) was close to that of the reference drug (73.9 %).
Based on these results, it can be reasonably suggested that the isolation of the active compound(s) from these extracts may yield novel analgesic agents.Moreover, findings justify the folkloric use of the plant for treating pain and inflammatory diseases.

Nutritional value of C. cinerea
Knowledge of dromedary-desert rangelands relationships is an essential element in the management and eco-development of the northwest Algerian Sahara which constitutes the habitat of various plants grazed by this animal.The dromedary is the only breeding species able to use these Saharan plants, making them valuable for the production of milk and meat, which constitute an important food resource for indigenous peoples [53].The nutritional value (energy and nitrogenous values) of C. cinerea of the North Algerian Sahara have been evaluated [53].The nutritional value assessment (based on chemical composition of this species) showed low values of fodder unit milk and of fodder unit meat (0.31 and 0.27, respectively).Nitrogenous value assessment of C. cinerea showed that the values of digestible protein in the small intestine limited by nitrogen (PDIN) and digestible protein in the small intestine limited by energy (PDIE) were 34.01 ± 1.14 g and 27.86 ± 2.72 g, respectively.

CONCLUDING REMARKS
This review is aimed at providing comprehensive and up-to-date information on research on the traditional uses, phytochemistry and biological activities of C. cinerea.The reported pharmacological properties of this species confirm its traditional uses.The plant possesses antibacterial, antifungal, antioxidant, herbicidal, anti-diarrheal and analgesic properties.Most of the therapeutic effects may be due to the presence of various phytoconstituents such as saponins, essential oil, tannins, flavonoids, steroids, and terpenoids.However, more investigations are needed to elucidate the exact mechanism(s) involved, as well as the nature of the bioactive components.

Figure 2 :
Figure 2: Photo of C. cinerea [16] GEOGRAPHICAL DISTRIBUTION OF C. CINEREA Cotula cinerea is a xerophytic plant; it thrives in desert conditions with an average annual rainfall of 100mm.The plant favors sand-loamy soils, and it is usually found on non-saline wadi beds on gravelly sandy soils [17].Geographically, it is widely distributed in North Africa especially in the Saharan regions of Algeria and Morocco, Red Sea region, Sinai, Qattara Depression and Mali [18].

Table 1 :
Classification of C. cinerea

Table 2 :
Essential oil yield of C.

Table 2
precipitation, air movement, sunshine duration, relative humidity, and temperature [37].Other factors that influence oil levels are the length of the day and altitude [38]; pedoclimatic conditions, as well as the ontogenic stage of the plant [39].It has been reported that the yield of essential oil increases with accentuation of water deficit and decreases with increases in salt concentration [40].In addition, essential oil content is influenced by the harvest stage, harvest time and mode of drying of the plant [41].Generally, the yield of essential oils is influenced by intrinsic factors such as the condition of the plant, harvest period, genetic factors, as well as extrinsic issues such as the floral procession, insect pests, pollinators, climate and nature of the soil [29].
increases with flowering [35].The accumulation of essential oils during the full-flowering period has been related to the attraction of pollinators, and to the increase in antifungal defense system during this period [36].The essential oil content also depends on The physicochemical properties of essential oils from C. cinerea have also been investigated.It has been reported that the essential oil of C. cinerea is yellowish and viscous, and it is characterized by olfactory properties that resemble those of Artemisia [31].Indeed, studies have indicated that at the fruiting stage, the essential oil of C. cinerea is characterized by a yellowish green color and viscous lingering odor, but at the flowering stage, the oil acquires a yellowish tinge [29].In addition, the essential oil possesses a very agreeable aromatic odor.The physical properties of the essential oils have also been studied with respect to density, refractive index and rotatory power, resulting in values of 0.864, 1.4610 and +115°, respectively [24].Moreover, numerous studies have been conducted on the composition of essential oils of C. cinerea essential oil from different geographical regions [24,29-33,42].The major chemical compounds present in C. cinerea essential oil from different regions are listed in Table

Table 3 :
Major chemical components essential oils from C. cinerea from different geographical locations

Table 4 :
Major chemical compounds in the essential oil of C. cinerea from different geographical locations

Antifungal activity of C. cinerea
antibacterial activity of C. cinerea extracts has been reported in a number of studies.Many researchers have investigated the antibacterial activity of essential oils from C. cinerea and reported that it possesses broad-spectrum antibacterial activity when tested by direct contact with pathogenic bacteria such as Enterococcus faecalis, Salmonnella heidelberg, Staphyloccocus aureus, Klebsiella pneumoniae, Echerichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, Enterococcus faecium, Morganella morganii, Citrobacter freundii, Proteus vulgaris, Acinetobacter baumannii, Bacillus subtilis and Micrococcus luteus [29,31,45].Some studies reported a relationship between the chemical structures of the major compounds in the essential oils of C. cinerea and its antibacterial activity.It has been reported that the ethylacetate and n-butanol extracts of the aerial parts of C. cinerea aerial part showed antibacterial activity against Pseudomonas fluorescens, Pseudomonas savastanoui, Bacillus sp., Bacillus brevis and Bacillus sphaericus [46], while the ethyl ether extract produced no antimicrobial activity against these bacterial strains.In another study, 70% ethanol, n-butanol, ethyl acetate and petroleum ether extracts of the aerial part of C. cinerea elicited antibacterial activities against Staphylococcus aureus,