Pharmacological potentials and toxicity effects of Excoecaria agallocha

© 2018 Eric Wei Chiang Chan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License -NonCommercialShareAlikeUnported License (http://creativecommons.org/licenses/by-nc-sa/3.0/). *Corresponding Author Eric Wei Chiang Chan, Associate Professor, Faculty of Applied Sciences, UCSI University, Cheras, Kuala Lumpur, Malaysia. Email: chanwc @ ucsiuniversity.edu.my; erchan @ yahoo.com Pharmacological potentials and toxicity effects of Excoecaria agallocha


INTRODUCTION
The genus Excoecaria of the family Euphorbiaceae comprises 37 tree species with acceptable names (The Plant List, 2013).Trees are distributed throughout tropical Africa, Asia and Australia of which E. agallocha and E. indica occur in the mangroves (Duke, 2006;Yin et al., 2008).Several references are of direct relevance to the present review on E. agallocha.They are chemical constituents of plants from the genus Excoecaria (Yin et al., 2008); the chemistry and bioactivities of natural products from semi-mangrove flora (Li et al., 2009); E. agallocha (Euphorbiaceae): an overview (Rajeswari and Rao, 2015); an insight on E. agallocha (Kaliamurthi and Selvaraj, 2016); and ethnobotany, phytochemistry and pharmacology of E. agallocha (Mondal et al., 2016).
Excoecaria agallocha L. is a small deciduous tree up to 10-12 m tall (Duke, 2006;Giesen et al., 2007;Mondal et al., 2016).Trees are multi-stemmed and produce a copious amount of white latex, which is toxic, causing skin blistering and temporary blindness.The bark is greyish with vertical fissures and lenticels.Leaves are opposite, ovate or elliptic with a toothed margin and have two basal glands.They turn orange or red when old before shedding (Figure 1).The species is dioecious i.e. having male and female trees.Male flowers are larger than female flowers and scented (Figure 2).Fruits are a three-lobed capsule with dark brown or black seeds, resembling pepper corn.Commonly found at the landward side of mangroves, E. agallocha the species is distributed from South, Southeast and East Asia extending to Australia and the west Pacific (Duke, 2006;Giesen et al., 2007).In China, the species is widely distributed along the southern coast, stretching from Zhejiang to Guangxi and Hainan (Li et al., 2010).Trees of E. agallocha grow gregariously with abundance varying from 170 stems/ha at Tok Bali in Kelantan, Malaysia (Kasawani et al., 2007) to 533 stems/ha in the Sundarbans, Bangladesh (Kamruzzaman et al., 2018), and to 1294 stems/ha in Kerala, India (Vijayan et al., 2015).Closely related is E. agallocha is E. indica, which is monoecious i.e. having male and female flowers on the same tree (Ragavan et al., 2015).Trees of E. agallocha have religious significance.At the Hindu temple of Chidambaram in India, the local community prays to the species as sacred plants (Kaliamurthi and Selvaraj, 2016;Agoramoorthy et al., 2007).The first newsprint mill in Bangladesh was located along the Bhairab river at Khalishpur in Khulna (Alam, 2006;Baba et al., 2013).The mill, which started operation in 1959, used E. agallocha (gewa) wood as raw material.The toxic latex of E. agallocha is known to cause skin irritation and blistering, and temporary blindness (Laith and Najiah, 2014).In countries of Southeast Asia, the latex has been used as fish poison.In Thailand, its bark and wood have been used as traditional medicine to treat flatulence (Karalai et al., 1994).The plant is traditionally used for the treatment of ulcers, rheumatism, leprosy, and paralysis in the coastal regions of South China (Li et al., 2012).In Okinawa, Japan, the resinous E. agallocha wood has been used to substitute agarwood (jinko) as incense (Konoshima et al., 2001).

Antiviral
There was increasing research interest on E. agallocha when a novel phorbol ester (12-deoxyphorbol-13-[3E,5E]-deca-3,5-dienoate) isolated from its leaves and stems was found to be a potent inhibitor of HIV-1 replication with an IC 50 value of 6.0 nm (Erickson et al., 1995).Soon after, screening of mangrove plant extracts for anti-HIV activity in MT-4 cells showed that the ethanol leaf extract of E. agallocha displayed potent activity (Premanathan et al., 1996).Values were 7.3 and 30 µg/ml for 50% inhibition of HIV activity and for 100% inhibition of HIV adsorption, respectively.Recently, the active ethanol stem fraction of E. agallocha was reported to inhibit the reverse transcriptase enzyme which is responsible for the synthesis of proviral DNA (Patil et al., 2011).The fraction showed 34% of inhibition, comparable with the standard drug azidothymidine (36%).When screened for inhibition of Epstein-Barr virus (EBV) in TPAactivated Raji cells, diterpenoids isolated from the wood of E. agallocha displayed stronger inhibitory effects than glycyrrhetic acid, an anti-tumour agent (Konoshima et al., 2001;Konishi et al., 1998c).Among the diterpenoids, ent-3α-hydroxy-beyer-15-ene-2one and excoecarin S exhibited the strongest anti-EBV activity.Polyphenols from the leaves of E. agallocha were evaluated for their inhibitory effects against hepatitis C virus (HCV) (Li et al., 2012).Results showed that excoecariphenol D and corilagin inhibited HCV NS3-4A protease with IC 50 values of 6.9 and 3.5 µM, and inhibited HCV RNA in Huh 7.5 cells with EC 50 values of 12.6 and 13.6 µM, respectively.

Anti-inflammatory and analgesic
Diterpenoids including agallochaols isolated from stems and twigs of E. agallocha (Table 1) have been reported to possess anti-inflammatory activity (Li et al., 2010).They displayed potency in suppressing tumour necrosis factor (TNF)-α and interleukin (IL)-6 induced by lipopolysaccharide (LPS) in mouse macrophage RAW 264.7 cells by blocking NF-kB activation or AP-1 activation.In another study, E. agallocha was assessed for anti-inflammatory and analgesic effects (Babuselvam et al., 2012).The latex, leaf and seed extracts of E. agallocha (250 and 500 mg/ kg) displayed significant inhibition of carrageenan-induced rat paw oedema after 3 hours.Inhibition was 63%, 62% and 70%, respectively.The seed extract also showed maximum inhibition of 57% in the cotton pellet-induced granuloma test.Using the acetic acid-induced writhing and tail immersion tests, the seed extract showed significant analgesic activity.Earlier, the bark extract of E. agallocha at 500 mg/kg was reported to show significant reduction of 54% in acetic acid-induced writhing of mice (Subhan et al., 2008c).Recently, the antinociceptive effect of E. agallocha leaf extract (alkaline chloroform fraction) was attributed to rutin (Selvaraj et al., 2014).Docking simulation demonstrated that rutin interacted strongly with cyclooxygenase, forming a number of specific hydrogen bonds.

Other bioactivities
Leaf extracts of E. agallocha have anti-ulcer effect on NSAID-induced gastric ulcer rats (Thirunavukkarasu et al., 2009), anti-diabetic activity in alloxan-induced diabetic mice (Thirumurugan et al., 2009), enhance the non-specific immunity and disease resistance of fish (Laith et al., 2017), and inhibition of elastase and collagenase (Satyavani et al., 2018).The sedative effect on sodium thiopental injected mice (Subhan et al., 2008b), gastro-protective activity in albino mice (Subhan et al., 2008c), and anti-allergic activity in rat peritoneal exudate cells (Hossain et al., 2009) have been reported in the bark extracts of E. agallocha.Recently, the stem extract of E. agallocha has been reported to possess anti-hyperglycemic activity in glucose-loaded albino mice (Rahman et al., 2010).

TOXIC EFFECTS Larvicidal
Of the different extracts of E. agallocha aerial parts (methanol, ethanol, hexane, chloroform and aqueous) evaluated for mosquito larvicidal activity, the methanol extract exhibited significant inhibition against Aedes aegypti and Culex quinquefasciatus larvae (Thirunavukkarasu et al., 2011;Pradeepa et al., 2015).Another recent study reported that 100% mortality of A. aegypti, C. quinquefasciatus and Anopheles stephensi larvae was observed at 1200, 300 and 300 ppm of E. agallocha latex after 24 h exposure (Mendhulkar et al., 2017).The methanol leaf extract of E. agallocha showed significant anti-filarial activity against the various stages of development of Setaria digitata, a metazoan filarial parasite (Patra et al., 2009).After 24 h of treatment with the extract at 10, 50 and 100 μg/ml, 30%, 75%, and 90% of the parasite were found dead, respectively.The bark extract of E. agallocha resulted in the lethality of brine shrimp larvae with LC 50 value of 504 μg/ml and LC 90 value of 800 μg/ml (Shanmugapriya and Ramanathan, 2015).

Case report
A 15-year-old boy from the coastal suburb of southern Sri Lanka was splashed with toxic latex when cutting the branches of an E. agallocha tree (Kumarasinghe and Seneviratne, 1998).Within minutes, the boy experienced burning pain in the right eye, and in parts of the face, body and limbs contacted with the latex.He was admitted to the ophthalmology ward of the General Hospital in Matara.Ophthalmological examinations revealed superficial burns of the right eyelids, cornea and conjunctiva.Dermatological examination, two days later, showed erythema and oedema around the right eye and forehead, and blistering of the skin of the face, body, and limbs.On treatment with amoxycillin and paracetamol along with topical application of an antibiotic ointment containing neomycin, bacitracin, and polymyxin, the boy was discharged after five days.When reviewed after a month, the eye had normalized but the skin showed minor scarring and hypopigmentation.This case report on the toxic effects of E. agallocha latex was presented at the 19 th World Congress of Dermatology held in June 1997, Sydney, Australia (Kumarasinghe and Seneviratne, 1998).In an earlier study, the toxic E. agallocha latex which causes skin irritation and blistering has been attributed to three groups of diterpene esters of the daphnane and tigliane types (Karalai et al., 1994).All three groups exhibited no irritant activity on the mouse ear but when trans-esterified with alkali, these cryptic irritants become highly toxic Excoecaria factors.

CONCLUSION
In the mangroves, two species of Excoecaria occur.Information of the phytochemistry and pharmacological potentials of E. agallocha will serve as useful reference for E. indica, which is poorly studied.The latex of E. agallocha warrants further research before considering the beneficial pharmacological properties of the species.Notably are the toxic effects of the latex on humans, and on terrestrial and aquatic fauna of the mangroves.

Table 1 :
Classes and names of compounds isolated from Excoecaria agallocha.