A review on phyto-pharmacological potentials of Euphorbia thymifolia L.

Euphorbia thymifolia L. (Euphorbiaceae) is a small branched, hispidly pubescent, prostate annual herb, commonly known as laghududhika or choti-dudhi. The leaves, seeds and fresh juice of whole plant are used in worm infections, as stimulant, astringent. It is also used in bowel complaints and in many more diseases therapeutically. The present work is an extensive review of published literature concerning phytochemical and pharmacological potential of E. thymifolia. Data was searched and designed using various review modalities manually and using electronic search engines with reference to all aspects of E. thymifolia and was arranged chronologically. Complete information of the plant has been collected from the various books and journals since the last 32 years, internet databases, etc., were searched. Compiled data reflects the safety and therapeutic efficacy of the plant. This will be helpful for researchers to focus on the priority areas of research yet to be explored and in scientific use of the plant for its wide variety of traditional therapeutic claims and also as to find out new chemical entities responsible for its claimed traditional activities.

INTRODUCTION

Euphorbia thymifolia is commonly known as laghududhika or choti-dudhi.[12] Over half a century after launching therapy for treatments, phytochemicals have become an important part of drugs. Actually, 70% of drugs approved between 1940 and 2002 are either natural products or have been developed based on knowledge gained from natural products.[3] Depending on the primary information available on this plant, further studies such as phytochemical and pharmacological standardization of extracts, isolation and identification of active constituents, pharmacological studies on isolated compounds, mode of action, formulation development, clinical and toxicological efficacy etc. are still remain to be explored so far.

EUPHORBIA THYMIFOLIA L., SP. PL. 454. 1753

Synonyms

Anisophyllum thymifolium (L.) Haw.; Aplarina microphylla (Lam.) Raf.; E. thymifolia F. laxifoliata Chodat and Hassl.; Ephedra foliata Buch.-Ham. ex Dillwyn; Epipactis microphylla Lam.; E. rubicunda Blume; E. rubrosperma Lotsy; Chamaesyce microphylla (Lam.) Soják; C. rubrosperma (Lotsy) Millsp.; C. thymifolia (L.) Millsp.[456789]

Plant description

Softly hispid prostrate herbs. Stem puberulous, slender, cylindrical, pale green but often pink in color when fresh, becoming grayish green or dark purplish on drying. Stems are with white latex, spreading on the ground, 10-20 cm in length with a diameter from 1 to 3 mm; branches radiating, slender, reddish and pubescent. Leaves are simple, opposite, elliptic, oblong or ovate, 4-8 mm long and 2-5 mm wide with rounded apex, oblique base, small, unequal sided at base. The petiolate, 3-6 mm long, 2-4 mm wide, mostly green, but often coppery red when fresh, becoming grayish green or dark purplish on drying. The lamina is oval-oblong or obliquely oblong. Apex is obtuse or rounded. Margin is dentate towards apex and smooth toward the base and venation is reticulate. Petiole is small, thin, slender, pale green and often pinkish in color. Cyathia in axillary clusters. Involucre campanulate, c. 8 mm long; glands 4. Male flowers 1-4, ebracteolate. Female laterally pendulous; ovary tomentose; style 3-forked from base. Fruits are ovoid-globose, acutely 3-lobed, almost sessile capsule 1 mm × 1 mm base truncate, short-hairy. They are cocci when mature. Seeds are conical, log, ovoid and obtusely quadrangular, up to 1 mm long, acutely 4-angled, reddish brown without caruncle. The photograph of E. thymifolia as shown in Figure 1.[710111213]

Figure 1

Photograph of Euphorbia thymifolia

PHENOLOGY: JUNE-NOVEMBER

Seed germination

Seeds can germinate immediately after dispersal from the plant, if the conditions are favorable. Seeds of E. thymifolia have no dormancy period. Red form has a germination of 68% and green form of 48% only. Dispersal of seeds occurs by an explosive mechanism of the capsule described by Ridley in 1993. Germination of seeds and seedling morphology of this species are very similar to that of Euphorbia hirta Linn. It is often difficult to distinguish the seedlings of these two species up to the 4-leaved stage. The differences are marked only the leaves that develop later.[14]

Seeds are minute, quadrangular, bluntly pointed with 5-6 shallow transverse furrows. The length varies from 887 to 926 μ and the breadth from 434 to 532 μ. The hape index as indicated by the ratio length/breadth varies from 1.7 to 2.1. The average weight of seed is 0.13 mg.

OCCURRENCE AND DISTRIBUTION

It occurs throughout India in plains and low hills, ascending to 5,500 ft. in Kashmir but also distributed throughout tropics except North Australia.[14] E. thymifolia is frequently found in waste lands, along road-sides and wall sides under humid conditions, gravel walks, grasslands, abandoned fields, etc.[14] The geographical distribution map of E. thymifolia as shown in Figure 2.

Figure 2

Geographical distribution map of Euphorbia thymifolia (ENVIS database)

Ecology

Two ecotypes of species i.e., red form and green form have been recognized. Red form has a higher percentage germination of seeds than green. E. thymifolia thrives all-round the year being able to withstand cold during winter and drought during hot and dry months of summer. The plant continues to flower and fruit in all seasons. The plant has wide-range of tolerance with regard to moisture in the substratum. There is no appreciable difference in the stomatal frequency and stomatal index in the red and green forms of E. thymifolia. Higher stomatal frequency in the case of sun leaves compared with shade leaves is due to drier conditions in the open than shade. Three populations within the red ecotype of E. thymifolia showed very diverse responses to calcium in the soil in regard to their growth performance under competitive and non-competitive conditions. In nature, these populations occupy soils with markedly different levels of exchangeable calcium in the soil. Malla soil was found to be highly calcareous compared to Chandigarh soil, Shiwalik soil being intermediate. The soil analysis parameters and their description as shown in Table 1.[15]

Table 1

Soil analysis

USES

Traditional

E. thymifolia is traditionally used as a blood purifier, sedative, haemostatic; aromatic, stimulant, astringent in diarrhea and dysentery, anthelminthic, demulcent, laxative; and also in cases of flatulence, constipation; in chronic cough; as an antiviral in bronchial asthma and paronychia.[1112161718] The dried leaves and seeds are given along with butter-milk to children in bowel complaints. Root is given in amenorrhea and gonorrhea. The oil is used in medicinal soaps for the treatment of erysipelas. Oil is also used as a spray to keep off flies and mosquitoes. It is also used as a vermifuge for dogs and farm foxes. Plant juice is employed in southern India as a cure for ring worms. Juice the plant powder is given with wine as a remedy for bites of venomous reptiles. It is applied with ammonium chloride to cure of dandruff.[121112181920] The fresh plant is considered vulnerary and galactagogue, used in ophthalmia and other eye troubles, ardor, sores, atrophy, dysentery and breast pain.[21] Caraka prescribes dugdhika is an ingredient of vegetable soup for diarrhea, painful bleeding piles. According to Bhāvaprakaśa, dugdhikā is expectorant and cures aggravated cough, skin disease and parasitic infections. It promotes conception, possesses aphrodisiac and age-sustaining properties.[111222] The plant is also used as an anti-pyretic, in chronic cold, menstrual disorders, urinary tract infections, skin diseases such as leprosy, measles and other skin eruptions. The crushed plant is rubbed on the head as an irritating rubefacient to promote hair growth in cases of alopecia. The latex is said to be useful in acne vulgaris and as a tonic in menorrhagia.[1112132324] The ayurvedic and siddha properties of E. thymifolia are listed in Table 2.

Table 2

Ayurvedic and Siddha properties

Phytochemistry

E. thymifolia yields a green essential oil with a peculiar pungent odor and irritating taste.[1] It has been attributed various phytochemical constituents in various parts with their categories as shown in Table 3. The structures of some isolated compounds shown in Figure 3. The plant has been reported to have some physical constituents as shown in Table 4. E. thymifolia contains crystalline alkaloidal principle allied to quercetrin.[2] It has also reported to contain as a large number of phenolics.[25]

Table 3

Chemical constituents present in E. thymifolia

Figure 3

Isolated compounds of Euphorbia thymifolia

Table 4

Physical constituents present in E. thymifolia (whole plant)

PHARMACOLOGICAL STUDIES

E. thymifolia has been reported for its various actions as follows;

Co-carcinogenic

Co-carcinogenic activity is due to phorbol derivatives.[23]

Antihyperglycemic

Antihyperglycemic activity was analyzed using oral glucose tolerance test. Mice were given various doses of the extract, followed by glucose (2 g/kg body weight), 1 h after administration of the extract. Serum glucose levels were measured 2 h after glucose administration. The extract caused a significant dose-dependent reduction in serum glucose levels in mice, when administered at doses of 50, 100, 200 and 400 mg/kg body weight as compared to the control animals. The highest reduction of serum glucose (60.5%) was observed at a dose of 400 mg/kg. In comparison with a standard antihyperglycemic drug glibenclamide, when administered at a dose of 10 mg/kg body weight, lowered serum glucose levels by 48.6%.[29]

Antinociceptive

Antinociceptive activity was evaluated using acetic acid induced writhing. All mice received intraperitoneal injection of 1% acetic acid at a dose of 10 ml/kg body weight. To ensure bioavailability of acetic acid, a period of 5 min was given to each animal following which period the number of writhings was counted for 10 min. The extract also demonstrated a significant dose-dependent antinociceptive activity compared to control animals. At a dose of 400 mg/kg body weight, the number of abdominal writhings was inhibited by 40.9% when compared with 49.0% inhibition obtained with a standard antinociceptive drug aspirin, administered at a dose of 200 mg/kg body weight.[29]

Anti-herpes simplex virus (HSV)-2

In-vitro anti-HSV-2 activity was studied using ethyl acetate (extract and 3-O-galloyl-4,6-(S)-hexahydroxydiphenoyl-d-glucose (3OG46HG) of E. thymifolia. The results demonstrated that the ethyl acetate extract and 3OG46HG affected virus infectivity in a dose-dependent manner. Ethyl acetate extracts significantly reduced virus infectivity at a concentration of 4.0 μ/ml, whereas, 3OG46HG obviously diminished virus infectivity at a concentration of a 0.5 μ/ml. The virucidal ability of the ethyl acetate extract was affected by the incubation period, but not by the incubation temperature. In the case of the action of 3OG46HG against HSV-2, the effects of incubation time and temperature were negligible.[30] Anti-HSV-2 or antiviral activity was also evaluated by using fractions of 3-O-galloyl-4,6-(S)-HHDP-D-glucose and ethyl acetate.[31]

Antioxidant or free radical scavenging/anti-lipid/anti-superoxide

Antioxidant activity of the ethanol extract of the whole plant of E. thymifolia has been evaluated in both in-vivo and in-vitro experimental models by estimating the malondialdehyde content of rat brain, which is one of the products of the lipid peroxidation. The ethanolic extracts of the plant showed significant inhibition of lipid peroxidation level comparable to that of vitamin E used as standard.[4] Antioxidant or free radical scavenging, anti-lipid and anti-superoxide formation activities of E. thymifolia were investigated using fractions i. e., MeOH, CHCl (3), EtOAc, n-butanol, water and pure compounds (3-O-galloyl-4,6-(S)-HHDP-D-glucose, rugosin B and 1,3,4,6-tetra-O-galloyl-K-beta-D-glucose), with the exception of the organic aqueous fraction in the anti-lipid and anti-superoxide formation assays. The range of IC50 of anti-lipid formation, anti-superoxide formation and free radical scavenging assays for all fractions and pure compounds were 2.81-7.63, 0.03-2.18 and 0.013-2.878 mg/ml, respectively. Electron spin resonance studies showed that water extract and pure compounds of E. thymifolia exhibited superoxide radical and hydroxyl radical scavenging activities.[31] Antioxidant activity was also evaluated using ethanolic extract of the whole plant. The extract inhibited nitric oxide free radical, which was estimated by Griess's method that involves the use of griess reagent (1% sulphanilamide, 2% phosphoric acid and 0.1% naphthyl ethylenediamine dihydrochloride). The extract was found to produce significant anti-oxidant activity and phytochemical screenings could also be conducted.[32]

Anti-inflammatory

Anti-inflammatory activity was evaluated using ethanolic extract of the whole plant by carrageenan-induced rat paw edema method. The extract in the dose of 100 mg/kg body weight caused a comparable reduction in edema with that of standard drug, Indomethacin (10 mg/kg) The extract was found to produce significant anti-inflammatory activity.[32]

Antispasmodic

Antispasmodic action was analyzed using ethanolic extract of E. thymifolia. It was found that the ethanolic extract was able to moderately inhibit the growth of Plasmodium falciparum.[33]

Antifungal

Antifungal activity of ethanolic extract of E. thymifolia against fungal strain Candida albicans was reported.[33]

Antibacterial

Antibacterial activity was studied using ethanolic extract of E. thymifolia against Staphylococcus aureus, Bacillus pumilis, Bacillus subtilis. Ethanolic extract showed very significant antibacterial activity.[33] Antibacterial activity of ethyl acetate (0.45 mg/ml) and chloroform (0.7 mg/ml) extracts of E. thymifolia against Escherichia coli and Shigella flexneri. Both extracts was inhibited the growth of E. coli and S. flexneri by in-vitro studies while ethyl acetate extract was active only against S. flexneri by in-vivo.[34]

Larvicidal

Larvicidal activity of crude hexane, ethyl acetate, petroleum ether, acetone and methanol extracts of five medicinal plants such as Abutilon indicum, Aegle marmelos, E. thymifolia, Jatropha gossypifolia and Solanum torvum were studied for their toxicity against the early fourth-instar larvae of Culex quinquefasciatus. The larval mortality was observed after 24 h and exposure. All extracts showed moderate larvicidal effects.[35]

Antimicrobial

E. thymifolia exhibits antimicrobial activity due to alkaloids.[23] Antimicrobial activity of E. thymifolia was evaluated by cylindrical cup plate method using standard cultures. Six standard bacterial cultures viz., E. coli ATCC-8739, B. subtilis ATCC-6633, S. aureus ATCC-25923, Klebsiella pneumonia AYCC-10031, Pseudomonas aeruginosa ATCC-27858, Salmonella typhi and three fungal strains viz., Aspergillus niger ACC-16404, C. albicans ATCC-10231, Penicillium chrysogenus were used for the activity. The fresh latex showed maximum activity when compared with diluted latex, dried latex, fresh juice and ethyl acetate, butanol, chloroform extracts of fresh plant. Ciprofloxacin and fluconazole were used as standard drugs.[36]

Antibronchial asthmatic

Various workers have reported E. thymifolia to be beneficial in the treatment of Bronchial asthma, on the basis of their clinical and experimental studies conducted on the mixture of two plants, i.e., E. thymifolia and E. prostrate. Both the plant species have two ecotypes- red and green. This study deals with evaluation of the efficacy and mode of action in the treatment of bronchial asthma using water soluble fraction of total alcoholic extract of the plants. The study revealed that the drug causes relaxation of smooth muscles by virtue of which the spasm of bronchial muscles during an acute attack of bronchial asthma, is relieved and thus exhibits its beneficial effect.[37]

Anthelmintic

Anthelmintic activity of methonolic and aqueous extracts of E. thymifolia were investigated against Pheretima posthyma and Ascaridia galli. Various concentrations of the extracts showed significant anthelmintic activity in a dose dependent manner.[38]

Laxative

Capasso et al. studied the laxative activity of crude aqueous extract of leaves of E. thymifolia at doses 100 and 200 mg/kg, in albino rats compared with standard drug agar-agar (300 mg/kg, p.o.) in normal saline. The rats were fasted for 12 h before the experiment. After 8 h of drug administration the feces were collected and weighed. The rats which were given the extract produced significant laxative activity in dose dependent manner. Laxative activity may be attributed to the presence of anthracene derivatives in the leaves.[3940] Laxative activity was also studied using crude ethanolic extract and fractions of E. thymifolia. The extract showed significant laxative activity in a dose dependent manner. Fractions of the extract were noted to potentiate the activities.[41]

Diuretic

Diuretic activity of crude ethanolic extract and fractions of E. thymifolia were evaluated. The extract showed significant diuretic activity in a dose dependent manner. Fractions of the extract were noted to potentiate the activity.[41]

Clinical or therapeutic evaluation

Clinical trials with triturated fresh leaves of E. thymifolia proved its efficacy in paronychia (common nail bed infection) when applied at early stage. In a clinical trial on 15 patients of bronchial asthma (Tamakaśvāsa) ghanasattva (solidified water extract) of E. thymifolia and E. prostrata was administered 12 g/day (in equal four divided doses) for 14 days. 33% of patients were relieved and 60% showed improvement. The rest showed no significant improvement.[10]

Toxicity studies

Toxicity of E. thymifolia latex has been reported, it causes dermatitis and is vesicant to skin of sensitive individuals.[42]

Substituent's and adulterants

Substituent's and adulterants of E. thymifolia are E. pilulifera, E. hypericifolia and Euphorbia hirta because they share the same regional name Dudhi, i. e. Dugdhikā.[20]

CONCLUSION

The current review reveals that, E. thymifolia was found to be having potent antihyperglycemic, antinociceptive, larvicidal, anti-HSV-2, antioxidant, anti-inflammatory, antibacterial, anthelmintic, and laxative activities. This plant has been reported to contain quercetrin, cymol, carvacrol, 2-sesquiterpenes, salicylic acid, etc., phytoconstituents. Furthermore, it contains steroids, terpenoids, glycosides, essential oils, minerals, tannins, flavonoids, large number of phenolics. It was also observed that there is no patent so far on this plant. Therefore, further studies of standardization of extracts, isolation and identification of active constituents, pharmacological studies on isolated compounds, mode of action, formulation development, clinical and toxicological efficacy remain to be explored so far. These studies will be helpful for modern drug development and serve the purpose of Ayurvedic formulation development in curing and treating diseases and to prove clinical safety, reliability and efficacy. This plant can be used as a cheap source of active therapeutics.