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Review Article

Ethnomedicinal uses, phytochemistry and pharmacological aspects of the genus Premna: a review

Roza DianitaDrug and Herbal Research Center, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaView further author information
&
Ibrahim JantanDrug and Herbal Research Center, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, MalaysiaCorrespondence[email protected]
View further author information
Pages 1715-1739 | Received 03 Aug 2016, Accepted 22 Apr 2017, Published online: 09 May 2017

Abstract

Context: The genus Premna (Lamiaceae), distributed throughout tropical and subtropical Asia, Africa, Australia and the Pacific Islands, is used in folk medicine primarily to treat inflammation, immune-related diseases, stomach disorders, wound healing, and skin diseases.

Objectives: This review exhaustively gathers available information on ethnopharmacological uses, phytochemistry, and bioactivity studies on more than 20 species of Premna and critically analyzes the reports to provide the perspectives and directions for future research for the plants as potential source of drug leads and pharmaceutical agents.

Methods: A literature search was performed on Premna species based on books of herbal medicine, major scientific databases including Chemical Abstract, Pubmed, SciFinder, Springerlink, Science Direct, Scopus, the Web of Science, Google Scholar, and ethnobotanical databases.

Results: More than 250 compounds have been isolated and identified from Premna species, comprising of diterpenoids, iridoid glycosides, and flavonoids as the most common secondary metabolites, followed by sesquiterpenes, lignans, phenylethanoids, megastigmanes, glyceroglycolipids, and ceramides. Many in vitro and in vivo studies have been conducted to evaluate the biological and pharmacological properties of the extracts, and isolated compounds of Premna species with antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, antihyperglycaemia, and cytotoxic activities.

Conclusion: The bioactive compounds responsible for the bioactivities of most plants have not been well identified as the reported in vivo pharmacological studies were mostly carried out on the crude extracts. The isolated bioactive components should also be further subjected to more preclinical studies and elaborate toxicity study before clinical trials can be pursued.

Introduction

The genus Premna was previously classified within the family Verbenaceae (Munir Citation1984), but has been transferred into the family Lamiaceae, subfamily Viticodeae (Harley et al. Citation2004; Olmstead Citation2010, Citation2012). Currently, this genus contains 200 species which are mainly distributed throughout tropical and subtropical Asia, Africa, Australia, and the Pacific Islands (Harley et al. Citation2004). There are 46 species recognized in the Flora of China (Tan & Li Citation2014) and 14 species occurring in the Flora Malesiana area (de Kok Citation2013). The word ‘Premna’ is derived from the Greek ‘premnon’, meaning tree stump, which refers to the short and twisted trunks of P. serratifolia L., the first collected species of this genus. Based on the shape and number of calyx lobes, the genus Premna has been subdivided into five sections: Holopremna Briq. (consisting of two subsections: Thyrsoideae and Corymbiferae), Odontopremna Briq., Gumira (Rumph. ex Hassk.) Briq., Premnos Briq., and Holochiloma Briq. (de Kok Citation2013).

Morphologically most species in the genus Premna are small trees or shrubs and rarely found as lianas (P. trichostoma Miq.) and pyroherbs (P. herbacea Roxb.). Some species have young twigs with a series of small decussate triangular scales at the base which will fall off once the branch is older. The leaves are usually decussate and hairy. A ridge is often present between the petioles. There are two shapes of calyx types. The first one has four isomorphic lobes, the shape remaining largely intact when the flower develops and when the fruits are formed. The second type has 0–5 lobes, usually heteromorphic. There are also two fruit types: a globose drupe-like fruit consisting of four fleshy mericarps with one seed each, and a clavoid, almost single-seeded, drupe-like and consisting of one fleshy mericarp (de Kok Citation2013).

Our review of the genus Premna is based on ethnomedicinal uses, phytochemical investigations, and pharmacological attributes. This review is comprised of more than 20 species of Premna from 150 publications. It is noted that some species have recently been considered as synonyms based on current plant taxonomy (The Plant List Citation2013). For example: P. obtusifolia R.Br., P. integrifolia Willd., and P. corymbosa var. obtusifolia (R.Br.) H.R. Fletcher are synonyms to P. serratifolia; P. japonica Miq. is a synonym to P. microphylla Turcz.; P. latifolia Roxb. as a synonym to P. mollissima Roth. However, in order to avoid any confusion, we continue to use the species names as referred to by the author(s) of the original papers. The detailed information gathered and critically analyzed in this review should be useful as reference for phytochemists, pharmacologists, medicinal chemists, biochemist, and food scientists to develop the bioactive compounds of the plants as potential nutraceutical, food additives, and pharmaceutical agents.

Ethnopharmacological uses

The diversity of species of Premna throughout the habitat region resulted in various traditional uses by the local people. The earliest report was on ethnomedicinal values of ten species of Premna throughout East and Southeast Asia, notably to treat malaria, stomach disorders, headache, cough, malaria and tuberculosis (Perry & Metzger Citation1980). Most lately, the extensive work by Quattrocchi (Citation2012) has recorded various ethnomedicinal uses of 29 species of Premna from numerous regions. Unlike other species which are endemic in certain region, P. serratifolia is widely distributed throughout the habitat region which explained its popularity in traditional medicine to treat various diseases or illnesses. In tropical Asia and East Africa, this species is notably used to treat neuralgia and headache, stomachic, fevers, colds and cough, and also to improve liver- and cardiac-related problems (Quattrocchi Citation2012). Other species, such as P. tomentosa Willd., are mostly used to treat stomach-related disorders by local people in Southeast Asia region. The local people in Burma, Thailand, Malay Peninsula and Indonesia use the leaves, root or the inner bark to relieve stomach ache discomfort/pain, for diuretic, or to treat diarrhea (Perry & Metzger Citation1980; Wiart Citation2000; Quattrocchi Citation2012).

Meanwhile, in Polynesian Islands, P. serratifolia is commonly used to treat infectious-related diseases such as leuchorrea, genital disease, cancer sores, bad breath and white tongue (Girardi et al. Citation2015). It is an interesting fact that few species were used in malarial treatment in different regions. For example, bark of P. angolensis Gürke was among traditional plants used to treat malaria and other fevers in S. Tomé and Príncipe islands in the Gulf of Guinea (do Céu de Madureira et al. Citation2002). The bark and the leaves of P. chrysoclada (Bojer) Gürke were used in treatment of malaria by the traditional health practitioners in Kilifi District, Kenya (Gathirwa et al. Citation2011). Quattrocchi (Citation2012) has listed two species of Premna that were used in malarial treatment in traditional medicine, P. foetida Reinw. Ex Blume leaves used in local communities in topical Asia, and P. glandulosa Hand.-Mazz. leaves used by the local community in China.

In the Phillipines, the leaves of P. odorata Blanco are used to treat phlegm and tuberculosis (Lirio et al. Citation2014). In China, India, Vietnam, Burma and Thailand, a few species have been recorded to treat skin diseases such as eczema, ringworms and boils, scabies, skin’s rashes and itching (Perry & Metzger Citation1980; Quattrocchi Citation2012; Sharma et al. Citation2014). The mucillagenous substance of P. ligustroides Hemsl. was recorded to be used topically as a sunstrike prophylactic in China (Perry & Metzger Citation1980). Jeevan Ram et al. (Citation2004) also reported the use of the stem bark of P. latifolia for wound healing. Khare (Citation2004, Citation2007) has highlighted four species of Premna (P. herbacea, P. integrifolia, P. latifolia and P. tomentosa) that are used in Ayurvedic medicine, either alone or together with other plant(s), and still available as over-the-counter medicine for local people. Known as ‘agnimantha’, ‘siru thekku’, ‘ghantu bharangin’, ‘agethu’, or ‘gineri’, the decoction of the leaves, stem bark, or roots have been used to treat asthma, rheumatism, neuralgia, diarrhea and stomach disorder, hyperglycaemic, and obesity. It is also used as a post-delivery tonic for women.

The details of species, part of the plant and the ethnomedicinal use of the Premna species are detailed in . Thus, we can categorize the ethnomedicinal values of the Premna species (i) as anti-inflammatory – either to treat asthma, rheumatism, gout, pains, fevers; (ii) to improve immune system and treat cold and cough; (iii) for stomach disorders such as diarrhea, dysentery, febrifuge, stomachache; (iv) for wound healing and treating skin diseases; (v) to treat bacterial (for example, tuberculosis, leuchorrea) and malarial infections; (vi) to treat migraine, headache, and neuralgia problems; and (vii) to treat hypertension, diabetes, liver-and cardiac-related problems.

Table 1. Some ethnomedicinal uses of Premna species

Phytochemistry

Essential oils

The genus Premna is not widely known to be rich in essential oil content. Nevertheless, previous studies have reported the contents of essential oils in a range of 0.056–0.102% in some Premna species (i.e. P. angolensis, 0.056%; P. barbata Wall. ex Schauer, 0.08–0.1%; P. coriacea C.B. Clarke, 0.08%; P. quadrifolia Schumach. & Thonn., 0.102%; P. integrifolia, not determined; P. tomentosa, 0.073%) (Narayan & Muthana Citation1953; Teai et al. Citation1998; Chanotiya et al. Citation2009; Rahman et al. Citation2011; Sadashiva et al. Citation2013; Adjalian et al. Citation2015). Among the compounds identified, 1-octen-3-ol, limonene, α-copaene, β-elemene, β-caryophyllene, and δ-cadinene were found as among well-distributed compounds in studied species in varied concentrations.

Hydrocarbons, fatty acids, ceramides and glyceoglycolipids

Hydrocarbons and lipid-related constituents [1–4, 7] have been identified in P. fulva Craib, P. crassa Hand.-Mazz., P. hainanensis Chun & F.C.How, P. odorata, P. integrifolia and P. serratifolia (Wei et al. Citation1991; Hang et al. Citation2008; Dai et al. Citation2010; Lirio et al. Citation2014). A phytochemical study on P. microphylla leaves has led to isolation of fatty acids [5–6], glyceroglycolipids [8–10] and ceramides [11–12] (Zhan & Yue Citation2003). Ceramides and glyceroglycolipid are major components of chloroplast membrane of the plant, which serve mainly as precursors of important signaling compounds/pathways in various cellular processes (Kolter & Sandhoff Citation1999). A few studies have reported ceramides and glycoglycerolipids to have immunodulatory activity as well as antitumor, anticancer and anti-inflammation properties (Van Veldhoven et al. Citation1992; Cateni et al. Citation2004; Ramos et al. Citation2006; Mbosso et al. Citation2012).

Sesquiterpenoids

Habtemariam et al. (Citation1993;) have reported the isolation of an antibacterial sesquiterpenoid, 7α-hydroxy-6,11-cyclofarnes-3(15)-en-2-one [13] from P. oligotricha Baker. Meanwhile, numerous monocyclofarnesane sesquiterpenes [14–19, 23–24] were isolated from P. microphylla leaves (Hu et al. Citation2013). An eudesmane [25] and an aromadendrane [26] were reported to be isolated from P. obtusifolia (Salae et al. Citation2012). In addition, Sudo et al. (Citation2000) reported the isolation of three megastigmane glycosides [20–22] from the leaves of P. subscandens Merr.

Diterpenoids

The genus Premna is mainly characterized by its diterpenoid constituents (Harley et al. Citation2004). One study has identified 91 skeletons of diterpenes within Lamiaceae, of which 13 skeletons were frequently identified (Vestri Alvarenga et al. Citation2001), and abietane diterpenes were highlighted as the most abundant and widespread within Lamiaceae, followed by labdanes, pimaranes, and clerodanes. Interestingly, our current review involving 17 species revealed that icetexanes and abietanes (including nor- and seco-abietanes) were the most common diterpene types occurred in the genus Premna, followed by pimaranes (including iso- and sandaraco-pimaranes), clerodane, labdane, podocarpanes and rosane (). At one time, icetexanes were found only in three genera of Lamiaceae: Coleus, Lepechinia, and Salvia. Habtemariam et al. (Citation1990) reported the presence of antibacterial clerodane diterpenes [29–30] from the leaves of P. schimperi Engl. A year later, two ent-labdane diterpenes [27, 28] were isolated from the aerial parts of P. oligotricha (Habtemariam et al. Citation1991). Another three clerodanes [31–33] were reported in P. tomentosa leaves (Chin et al. Citation2006). The labdane, ent-12-oxolabda-8,13(16)-dien-15-oic acid [27] and all clerodanes bear a free carboxylic acid unit attached to C-15 with oxygen substitution at C-12 and sp2-hybridization between C-13 and C-16. The structures of some of the diterpenes are shown in .

Figure 1. Chemical structures of some diterpenoids obtained from Premna species.

Figure 1. Chemical structures of some diterpenoids obtained from Premna species.

Table 2. Isolated compounds from genus Premna (Lamiaceae).

Eighteen abietanes [34–51], a nor-abietane [52], two secoabietanes [54, 55] and a abietane [53] have successfully been identified in P. latifolia (Rao et al. Citation1978; Rao & Vijayakumar Citation1980), P. integrifolia (Yadav et al. Citation2010), P. obtusifolia (Salae et al. Citation2012) and P. serratifolia (Habtemariam & Varghese Citation2015). Oxygenated substitution at C-12 of abietane is common within this genus and sometimes the substitution may occur at C-1, C-6, C-7, C-11, C-14 and C-16. While nor-abietane [52] is characterized by loss of methyl at C-10, this methyl moves from C-10(α) to C-5(β) in a novel abietane, premnolal [56]. Additionally, two abietane derivatives [56, 57], known as podocarpanes, were isolated from P. latifolia var cuneata C.B.Clarke which do not have isoprenyl substitution at C-13. Two pimaranes [58, 59] with rare 1,3-dihydroxy and 2-hydroxy, respectively, were isolated from P. integrifolia (Yadav et al. Citation2010). Two isopimaranes [60–61] were reported to be identified in P. obtusifolia (Salae et al. Citation2012) along with other pimarane-related type, a rosane [68]. Earlier, several studies (Rao & Rao Citation1978; Rao & Vijayakumar Citation1980; Rao et al. Citation1982) reported the occurrence of six sandaracopimaranes [62–67] from P. latifolia and P. latifolia var cuneata with common α-hydroxyl substitution at position C-8. The iso- and sandaraco-pimaranes are the isomeric 13-Meβ and 17-Meα forms of pimarane. Though rosane could be found as both 13-C enantiomers, its structure is distinguishable by migration of methyl at C-10 at pimarane to the C-9 position.

Recent studies have identified the genus Premna as rich in icetexane diterpenes. As of this review, 20 icetexanes have been isolated from Premna species including three dimeric icetexanes and three rearranged icetexanes. Extensive phytochemical work on P. obtusifolia has led to the isolation of four icetexanes [77–80], two dimeric icetexanes [86–87] and three rearranged icetexanes [69–71] (Salae et al. Citation2012; Salae & Boonnak Citation2013). An icetexane [72] was also isolated from P. herbacea [72] (Sandhya et al. Citation1988; Murthy et al. Citation2006), while several icetexanes [73–76, 81–82] were obtained from P. tomentosa (Hymavathi et al. Citation2009; Ayinampudi et al. Citation2012). Icetexanes [83–85, 88] were also isolated from P. latifolia (Suresh et al. Citation2011a, Citation2011b). Hypothetically, icetexane is derived from rearrangement of methyl at C-10 of abietane skeleton to form 6-7-6 tricyclic diterpene. Common substitutions occurs at C-11 and C-12, mostly as hydroxyl [72–81] which might further rearrange and form a five-member ring [82–85].

Sterols and triterpenes

Three skeleton type of pentacyclic triterpenes have been reported from the genus Premna, i.e. lupane, oleanane and ursane. Three lupane-type diterpenes [89, 90, 94] have been identified in P. fulva (Quan et al. Citation1989), P. hainanensis (Dai et al. Citation2010) and P. tomentosa (Hymavathy et al. Citation2009; Ayinampudi et al. Citation2012) while three derivatives of lupeol [91–93] have been isolated from P. fulva (Wei et al. Citation1991). Further studies also reported the presence of four oleanane-type triterpenes [95–98] which were distributed in P. crassa, P. fulva, P. hainanensis and P. microphylla (Wei et al. Citation1990, Citation1991; Dai et al. Citation2006, Citation2010; Zhan et al. Citation2009). Additionally, four ursane-type diterpenes [99–102] were identified in P. fulva (Dai et al. Citation2006; Niu et al. Citation2013), P. microphylla (Hu et al. Citation2013) and P. tomentosa (Chin et al. Citation2006). Common plant sterols, such as stigmasterol [105], and their glycosides [106,107], are widely distributed among P. crassa, P. fulva, P. hainanensis, P. latifolia and P. odorata (Rao et al. Citation1981; Rao & Rao Citation1981; Wei et al. Citation1991; Ghosh et al. Citation2014; Lirio et al. Citation2014). Two cholestanes [103–104] were isolated from P. serratifolia (Wang et al. Citation2011), and stigmastene-glycoside [108] was identified in P. fulva (Dai et al. Citation2006) and P. hainanensis (Dai et al. Citation2010).

Iridoid and iridoid glycosides

Iridoids are monoterpene lactones which usually occur in plants as glycosides and sometimes are known as monoterpene alkaloids. They can be found in dicotyledone angiosperms within the superorders Corniflorae, Gentianiflorae, Lamiiflorae and Loasiflorae (Ghisalberti Citation1998). Their structures are based on cyclopentan[c]pyran skeleton represented as iridane (cis-2-oxabicyclo[4.3.0]nonane) and seems to be biosynthesized via alternative cyclization of geranyl diphosphate (Sampaio-Santos & Kaplan Citation2001). The name ‘iridoid’ itself comes from iridodial and related compounds isolated from the defense secretion of Iridomyrmex species (Tietze Citation1983). Classification of naturally occurring iridoids involves large groups, yet there are four distinguish classes i.e. the non-glycosidic iridoids, iridoid glycosides, iridoid acetal esters, and secoiridoid glycosides. Our current review has identified more than 53 iridoid glycosides within nine species of Premna (). Most of the isolated iridoids are catalpol derivatives [115–138, 148–168] although mussaenosidic acid, epiloganic acid and gardoside derivatives [139–147, 169] also could be identified in quite a great number. Majority of the iridoids are linked to their glycosides at C-1 though in catalpol, the glycoside could have linked to C-6. Interesting structure was displayed by compound 168, with two catalpol glycosides formed an ester to truxinic acid. Piscrosin D [148] was the only non-glycoside iridoid isolated from P. japonica (Otsuka et al. Citation1991b) and P. serratifolia (Wang et al. Citation2011), respectively. shows the structures of some of the iridoid and iridoid glycosides.

Figure 2. Chemical structures of some of the iridoids and iridoid glycosides.

Figure 2. Chemical structures of some of the iridoids and iridoid glycosides.

Phenylethanoids, aldehydes, alkaloids and lignans

Phenylethanoid glycosides (PhGs) are natural products which are structurally a glycosidic ester consisting of cinnamic acid and hydroxyl phenylethyl moieties attached to glycoside residue. Their structure may consist of monosaccharide, disaccharides, or trisaccharides, with the common glycosides being glucose, rhamnose, xylose, and apiose. They are found in many of the family Lamiaceae where acteoside or verbacoside [173] is common (Jiménez & Riguera Citation1994). Cistanoside F [170] and other ten PhGs [171–180] were isolated from the genus Premna (details in ), of which 174 contains a iridoid moiety attached to its glucose. Phenolic acids [181, 182] were reported in P. fulva and P. hainanensis (Wei et al. Citation1991; Dai et al. Citation2007, Citation2010; Chen et al. Citation2010) and several aldehydes [183–190] were isolated from P. integrifolia (Hang et al. Citation2008) and P. tomentosa (Hymavathi et al. Citation2009; Ayinampudi et al. Citation2012). One indole carboxylic acid [191] was also isolated from P. microphylla (Hu et al. Citation2013). Some alkaloids [192–194] were only identified in P. integrifolia (Basu & Dandiya Citation1947; Dasgupta et al. Citation1984). Lignans, a phenylpropanoid derivatives, were identified within 6 species of Premna and commonly found as furan lignans [199–202] (Rao & Rao Citation1981; Yuasa et al. Citation1993; Habtemariam et al. Citation1995) and furofuran lignans [203–209] (Yuasa et al. Citation1993; Habtemariam et al. Citation1995; Dai et al. Citation2007; Chen et al. Citation2010; Hu et al. Citation2013; Yadav et al. Citation2013) in the genus Premna except for compounds 195–198 which are dibenzylbutane lignans (Yuasa et al. Citation1993; Habtemariam et al. Citation1995) ().

Flavonoids, xanthones and chalcones

The occurrence of these flavonoids was reported from 13 species (). Most of the flavonoids were flavonols [224–239] and flavones [218–223, 240–247], although quite a number were flavanones [213–217], isoflavones [248–251] and one flavan-3-ol [212] (Dasgupta et al. Citation1984; Habtemariam et al. Citation1992; Balakrishna et al. Citation2003; Dai et al. Citation2007; Li et al. Citation2008; Chen et al. Citation2010; Monprasart et al. Citation2011; Pinzon et al. Citation2011; Wang et al. Citation2011; Yu et al. Citation2012; Hu et al. Citation2013; Lirio et al. Citation2014). A few flavonoid glycosides were also reported, identified as O-glycoside to either C-3 [238, 239], C-5 [240], C-6 [249–251], or C-7 [242, 243, 246, 247]; while two others [241, 244] attached to the glycoside residue through C-linkages at C-6 and/or C-8 (Rao & Rao Citation1981; Jyotsna et al. Citation1984; Zhong & Wang Citation2002; Dai et al. Citation2007; Hang et al. Citation2008; Chen et al. Citation2010; Wang et al. Citation2011; Yu et al. Citation2012; Ghosh et al. Citation2014). In addition, two xanthones [210, 211] were isolated from P microphylla (Wang & Xu Citation2003) and four chalcones [252–255] were reported in P. yunnanensis W.W.Sm. (Yu et al. Citation2012). The structures of some of the flavonoids are shown in . The skeleton structure resemblance of the flavonoids (C6-C3-C6), xanthones (C6-C1-C6) and chalcones (C6-C3-C6, without a heterocylic C-ring in the three-carbon α,β-unsaturated carbonyl system) suggested they shared a similar shikimate pathway via phenylpropanoid pathway in their biosynthesis whereas xanthones, in particular, might represent the modified shorthened forms of the C6-C3 system (Dewick Citation2001; Vogt Citation2010). However, some references stated that xanthones might possibly derive from shikimate acetate pathways (Velíšek et al. Citation2008).

Figure 3. Chemical structures of some flavonoids and flavonoid glycosides found in Premna species.

Figure 3. Chemical structures of some flavonoids and flavonoid glycosides found in Premna species.

Pharmacological activities

Antimicrobial, insecticidal, antileishmanial and antimalarial activities

Many studies have been carried out to evaluate the antibacterial and antifungal activities of extracts of Premna species (). Several studies have identified active antimicrobial compounds, mostly found as diterpenes [27, 29, 30, 48, 51, 55, 69. 70, 72, 78, 79, 80] (Habtemariam et al. Citation1990, Citation1991; Murthy et al. Citation2006; Salae et al. Citation2012) and few sesquiterpenes [13, 25] (Habtemariam et al. Citation1993; Salae et al. Citation2012). Earlier, Kurup and Kurup (Citation1964) has successfully isolated orange crystal substance from the alcoholic extract of the root bark of P. integrifolia that was active against Micrococcus aureus, Bacillus subtillis and Streptococcus haemolyticus (MIC 0-25 μg/mL) but inactive towards Escherichia coli, Salmonella typhosa and B. dysentriae.

Table 3. Antimicrobial and anti-inflammatory effects of the extracts of Premna species.

Compound 48 (Salae et al. Citation2012) appeared to have potent antibacterial activity with most of their MICs were <5 μg/mL, except for P. aeruginosa. Interesting broad spectrum antibacterial and antifungal activities were also showed by compound 72 (MIC 5-10 μg/mL), isolated from the roots of P. herbacea (Murthy et al. Citation2006). Another study by Lirio et al. (Citation2014) evaluated antitubercular activity against Mycobacterium tuberculosis of the leaves of P. odorata and its constituents. Although the extract showed relatively weak inhibitory activity, the fractions exhibited strong activity which eventually led to isolation of the active compound 4 (MIC90 8 μg/mL whilst rifampin 0.05 μg/mL and isoniazid 0.23 μg/mL).

The insecticidal activity of different extracts and essential oil of P. latifolia was tested against Spodoptera litura larvae, a polyphagus crop pest, by using leaf-dip method. The essential oil showed the highest growth reduction (56.83%) followed by chloroform, hexane and butanol fractions (43.93, 26.01 and 23.69%, respectively) (Kumar et al. Citation2011). Recent study on P. angolensis and P. quadrifolia evaluated the insecticidal and repellent effects of its essential oils against Sitoroga cerealella, an insect pest of rice stocks, using olfactometer and contact toxicity test (Adjalian et al. Citation2015). The results showed that both essential oils have insecticidal and repellent activities as indicated by rate of death of S. cerealella, percentage of repulsion, number of rice attacked and loss of weight of rice. The leaf extract of P. serratifolia showed strong activity against Leishmania donovani (IC50 4.4 μg/mL) but showed weak and/or no effect against Trypanosoma brucei brucei, Trichomonas vaginalis and Caenorhabditis elegans (Desrivot et al. Citation2007). It has been reported previously that clerodane diterpenes [28 and 29], isolated from P. oligotricha and P. schimperi, showed potent antileishmanial effects towards axenically cultured amastigotes of L. aethiopica (IC50 1.08 and 4.12 μg/mL, respectively). Both compounds also exhibited high selectivity towards L. amastigotes than the permissive host cell line, THP-1 cells or the promastigotes stage of the parasites (Habtemariam Citation2003).

Although widely used traditionally in malarial treatment by the Philippines, the ethanol extract of P. angolensis barks only showed weak antiplasmodial activity (IC50 180–500 μg/mL) towards both chloroquine sensitive and resistant strains of Plasmodium falciparum (do Céu de Madureira et al. Citation2002). However, the leaf extract of P. chrysoclada revealed high activity against chloroquinone sensitive and resistant strains of P. falsiparum (IC50 7.75 and 9.02 μg/mL) while the root extract only showed moderate activity (IC50 27.63 and 52.35 μg/mL). Further investigation also revealed that the leaf extract (dose 250 mg/mL) has strong ability to reduce the parasitized erythrocyte (9.26% parasitaemia) and to inhibit the parasite growth (65.08% chemo suppression) in Plasmodium berghei infected mice (Gathirwa et al. Citation2011).

Antioxidant, anti-inflammatory and immunomodulatory activities

Premna species are known to have high-antioxidant capacity, such as P. cordifolia Roxb. (Mustafa et al. Citation2010; Mohd Nazri et al. Citation2011), P. esculenta Roxb. (Mahmud et al. Citation2011), P. integrifolia (Gokani et al. Citation2011; Nguyen & Eun Citation2011), P. microphylla (Xu et al. Citation2010) and P. serratifolia (Rajagopal et al. Citation2014) (). The wide distribution of flavonoids and phenolics within this genus seems to contribute to this activity. Various methods were used to measure the antioxidant capacities such as radical scavenging (diphenylpicrylhydrazyl (DPPH), superoxide, nitric oxide NO, hydroxyl radicals), ferric reducing ability of plasma (FRAP), ferric thiocynate (FTC), lipid peroxidation, erythrocyte membrane stabilizing and β-carotene bleaching assays. Most of the radical scavenging capacity of the extracts has been correlated to their phenolic contents – the higher the phenolic content, the higher the antioxidant capacity. The presence of hydroxyl group (OH) and/or unsaturated bond are suggested to play the main role in capturing the radical oxygen species (ROS).

Secondary metabolites such as flavonoids, xanthones, chalcone and other phenolic compounds with high-hydroxyl group substitution are hypothetically contributing to the high antioxidant activity of the plant. For example, two flavone glycosides [213, 214] from P. latifolia leaves significantly inhibited oxidation of DPPH (IC50 22.5 and 16.0 μg/mL, respectively) (Ghosh et al. Citation2014). Furofuran lignans [208, 209] and iridoid glycosides [150, 154, 161, 165] might contribute to antioxidant activity of the stem bark of P. integrifolia when evaluated with radical scavenging (DPPH and NO) and ferric reducing antioxidant power (FRAP) assays (Yadav et al. Citation2013). Compounds 165 and 154 possessed maximum radical scavenging activity (IC50 0.29 and 0.37 μM) in DPPH assay, followed by compound 209; while compounds 150 and 161 exhibited maximum reducing power in FRAP assay. Aldehyde derivatives [186 and 187] and icetexane diterpenes [81, 82] were thought to be potential free radical scavenger constituents from P. tomentosa (Ayinampudi et al. Citation2012; Ayinampudi Citation2013). The higher number of hydroxyl group in compound 82 (IC50 7.01 μg/mL) than compound 81 (IC50 24.80 μg/mL) reflected the higher antioxidant capacity of the former. Interestingly, this rule was not applied for compound 187 (IC50 20.58 μg/mL) which has three hydroxyl moieties, in comparison to compound 186 (IC50 20.83 μg/mL) which only has one hydroxyl moiety. Potential antioxidant activities were also exhibited by a series of icetexanes [73-76] from P. tomentosa towards DPPH, NO and superoxide scavenging assays, of which compound 76 demonstrated superior activities than the others and also on par with the standards (Naidu et al. Citation2014). Recent study also identified an aromatic diterpene [53] as antioxidant constituent from P. serratifolia with IC50 of 20.4 ± 1.3 μM towards DPPH assay (Habtemariam & Varghese Citation2015).

It is note worthy that although those studies showed some potential antioxidant capacities of some extracts of Premna species and its constituents, they do not necessarily reflect the molecular or in vivo activities. For example, the DPPH and FRAP assays are mostly based on the simple chemical reaction (Benzie & Strain Citation1996; Molyneux Citation2004). These cell-free antioxidant assays do not support the cellular physiological conditions, do not include particular biological substrates that need to be protected, may not encounter the relevant types of antioxidant at molecular level, may not describe the partition coefficient of the compounds, or other cellular factors. Cell-based antioxidant assays are considered more relevant and accurate in representing the in vivo conditions since they involve several aspects such as uptake, metabolism, and target site where the compounds might potentially worked within cells (Lü et al. Citation2010).

Inflammatory reaction occurs due to pathogen invasion into the body or other types of body injury which can cause injury to the tissues or cells as well. At macroscopic level, inflammation is indicated by reddened, swollen, hot, pain, and loss of function of the inflamed area. The loss of function is usually referring to simple loss of mobility in a joint due to pain or edema, or the replacement of functional tissue by the scar tissue. This inflammatory event usually will be followed by the release of mediators from the cells or plasma which modify and regulate the immune response (innate/nonspecific and specific immunological response) (Punchard et al. Citation2004). Hence, several studies have been conducted to evaluate the anti-inflammatory effect of the extracts of Premna species (). In addition, an extensive study by Salae et al. (Citation2012) identified several compounds from P. obtusifolia roots that exhibited potent anti-inflammation activity. Of 20 isolated compounds, four diterpenes [48, 49, 69, 70] showed potent in vitro lipopolysaccharide (LPS) induced NO inhibitor (IC50 6.1, 7.8, 1.7 and 6.2 μM) that were comparable to positive control, caffeic acid phenylester (IC50 5.6 μM). Meanwhile, megastigmane [21] only showed weak anti-inflammatory activity. Further structure-activity relationship analysis suggested that the presence of a hydroxyl group in an ortho-naphtoquinone skeleton provided stronger anti-inflammation activity. It was postulated that these active compounds might be responsible for the strong NO inhibitor activity of the hexane and dichloromethane extracts (IC50 4.3 and 6.1 μg/mL, respectively). Another species, P. integrifolia, also showed significant in vivo anti-inflammatory activity in both acute and chronic inflammation models; further in vitro study suggested inhibition of prostaglandin synthase and stabilization of plasma erythrocyte membrane might play role in the in vivo activity (Gokani et al. Citation2011).

Only one calculogenesis-related study has been carried out on Premna. The anticalculogenic activity of P. latifolia leaves and stems was evaluated in vitro by assessing oxalate crystal growth on gel medium in Hane’s tubes via single diffusion method over period of 30 days at the concentrations of 20 and 200 mg/mL (Aravindakshan & Bai Citation1996). The extract effectively reduced the size of oxalate crystal in comparison to negative control and further analysis by using scanning electron microscope showed development of cracks in the crystal interior and rupture tendency. These results concluded chemolysis as an anticalculogenic mechanism of this extract.

Interesting immunostimulant activity was exhibited by P. pubescens Blume and P. tomentosa leaves. In their in vitro studies, Devi et al. (Citation2003a, Citation2004a) used rat’s splenic lymphocytes and J770 macrophage cell culture which has been induced by using chromium, Cr(IV), to provide immunosuppressant condition. The results showed P. tomentosa inhibited the apoptosis of the Cr(IV)-induced cells by preventing the proliferation of the lymphocytes and the macrophages. At the same time, the extract has significantly reduced the ROS level by increasing the levels of the endogenous antioxidant enzymes such as glutathione (GSH), glutathione peroxide (GPx) and superoxide dismutase (SOD) enzymes, and reducing malondialdehyde (MDA) level. Meanwhile, in vivo study by Restuati et al. (Citation2014) in the antigen sheep red blood cell (SRBC)-induced immunostimulant rats, suggested that P. pubescens stimulated the immune response by increasing the number of leukocytes, immunoglobulin IgG and IgM, and lysozyme. In addition, the methanol extract of P. integrifolia roots also produced significant immunomodulatory activity in both specific and nonspecific immune responses following hemagglutinating antibody titer, plaque forming cell assay, delayed-type hypersensitive response, carbon clearance test (phagocytic activity) and E. coli-induced abdominal sepsis parameters (Gokani et al. Citation2007).

Cytotoxic activities

Traditional use of P. herbacea by the Thai to treat cancer has led to the evaluation of the rhizome extract of this species towards several cancer cell lines such as COR-L23, LS-174 T and MCF-7 (Itharat et al. Citation2004). The results turned out to be negative. However, another study by Dhamija et al. (Citation2013), showed that the root nodules extract had cytotoxic activity on brine shrimp lethality test (BSLT), Ehrlich ascites carcinoma (EAC) cells (trypan blue dye exclusion assay), and MCF-7 cell lines (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay). Ethanol extract and ethyl acetate fraction exhibited the most potent cytotoxic effect and further investigation on EAC-inoculated mice and Dalton’s lymphoma ascites (DLA) mice (250 and 500 mg/kg, orally) led to significant elevation of the mean survival rate and reduction of the solid tumor weight and volume. These findings were supported by hematological and antioxidant parameters. The EAC-inoculated mice model was used to evaluate antitumor activity of the ethanol extract of P. integrifolia; the findings were found to be comparable to the standard, 5-flurouracil (20 mg/kg) (Sridharan et al. Citation2011).

About 20 years ago Habtemariam (Citation1995) isolated diterpenes [27 and 29] from P. oligotricha and P. schimperi and suggested they possess cytotoxic property towards several cancer cell lines such as L929, RAW 264.7, HeLa, Sk.N.SH and ECV 304, with IC50 values of 1.5–35 μg/mL. Compound 30 was already known to exhibit a cytotoxic effect. Extensive phytochemical works and cytotoxicity assays on P. tomentosa (Chin et al. Citation2006; Hymavathi et al. Citation2009; Naidu et al. Citation2014) have led to the identification of several cytotoxic diterpenes [31-33, 99, 73–76]. Compounds [31–33] showed cytotoxic activity towards several cancer cell lines, Lu1, LNCaP, and MCF-7, but only 32 and 33 were active on in vivo hollow fiber assay towards the cell lines (Chin et al. Citation2006). Diterpenes [83-85] from P. latifolia exhibited cytotoxic effect towards HT-29 and Hep-G29 cell lines, especially compound 83 and 84 (IC50 0.04 and 0.18 μg/mL, respectively) (Suresh et al. Citation2011a). Another study has identified a diterpene [53] as one of the responsible compounds for cytotoxic property of P. serratifolia (Habtemariam & Varghese Citation2015). A similar study by Biradi and Hullatti (Citation2015) reported the cytotoxic properties of the extract of P. integrifolia and its unidentified compounds.

Antidiabetic/antihyperglycaemic and antihyperlipidemic activities

So far, four species of Premna has been studied for their antidiabetic properties. The most common method was using a chemically-induced diabetic animal model. Alloxan-induced hyperglycemic rats have been used to evaluate antidiabetic activity of ethanol extract of P. integrifolia at a dose of 250 mg/kg, to confirm the hypolgycaemic activity of this herbal based on the Indian folk medicines (Kar et al. Citation2003). This activity was further evaluated by Mali (Citation2013) using cafeteria diet induced mice (inbreed) through various parameters (body-mass index, blood glucose, lipid profile, histology valuation) and comparison with a standard drug (simvastatin). The findings indicated significant protective effect of the roots of P. integrifolia at doses of 200 and 400 mg/kg. P. corymbosa Rottler & Willd., also reduced blood glucose level in both normolgycaemic and alloxan-induced hyperglycemic rats, at doses of 200 and 400 mg/kg (Dash et al. Citation2005). Similar studies by Ayinampudi et al. (Citation2012) and Ayinampudi (2013) successfully identified two diterpenes [81, 82], and two aldehydes [185, 187] that were responsible for antihyperglycaemic activity of P. tomentosa root by inhibiting enzyme α-glucosidase in vitro (IC50 values were 22.58, 9.59, 18.41, and 12.11 μg/mL, respectively). One clinical study, based on the Ayurvedic system, evaluated the effectiveness of P. obtusifolia roots as an alternative treatment for diabetics (Ghosh et al. Citation2009). This 9-month study involved 50 patients with a history of obesity. The results showed significant reduction on body-mass index (BMI), atherogenic index and waist-hip ratio after 6 months while the uric acid and mid-triceps skin fold thickness were significantly reduced after 9 months.

The in vivo evaluation of antihyperlipidemic activity of herbal extract is normally done by determining the lipid profiles (LDL, HDL, triglycerides, cholesterol) and histology parameters. As mention earlier, P. tomentosa leaves extract showed antihyperlipidemic activity towards the animal model by improving lipid profile and reducing lipid metabolizing enzymes (Devi et al. Citation2004c). Meanwhile, Mali (Citation2013) reported the effect of P. integrifolia roots on lipid profile parameters of caffeinated-diet mice. Additionally, the antihyperlipidemic effect of the leaves and roots of P. esculenta was evaluated in vivo by using Poloxamer 407-induced hyperlipidemis mice and rats (Mahmud et al. Citation2011). The study was designed for single dose (mice, 500 mg.kg, i.p) and repeated dose (rats, 4 days, 250 mg/kg, p.o), and the results suggested the extract significantly reduced the serum total triglycerides, total cholesterol, LDL and VLDL levels which were comparable to the standard drug, atorvastatin.

Hepatoprotective and cardioprotective activities

Premna tomentosa has been extensively studied for its hepatoprotective activity. Devi et al. (Citation1998, Citation2004b, CitationCitationc, Citation2005) have evaluated the possible protection mechanisms of the extract of P. tomentosa leaves on acetaminophen-induced hepatoxicity in rats, which suggested via (i) reducing ROS and generating endogenous antioxidant enzymes in the liver (e.g. glutathione system, superoxide dismutase, catalase); (ii) improving lipid profile and reducing the activities of lipid metabolizing enzymes; (iii) decreasing the acetaminophen-induced membrane damage so that total membrane-bound ATPases would improve and eventually help maintaining active transport and balancing of Na+, Ca2+ and K+ in the liver and serum; and (iv) protecting the liver against mitochondrial damage as the mitochondrium contains enzymes that would catalyze the production of lipid peroxidation products and other toxic metabolites. Additionally, Hari Prasad et al. (Citation2006) postulated the protective mechanism of P tomentosa towards dimethylnitrosamine (DMN)-induced hepatic fibrosis was through decreasing the activation of liver stellate cells and accumulation of collagen and other connective tissue proteins. Recently Naidu et al. (Citation2014) reported that the in vitro (using HepG2 cells) and in vivo (using tBHP-induced hepatic damage mice) hepatoprotective activity of compound 76 increased the viability of hepatic cells and decreased the elevation of serum transferases (SGOT/SGPT) and oxidative damage, including lipid peroxidation. P. corymbosa and P. serratifolia also showed protective activity on chemically induced (carbontetrachloride (CCl4) and paracetamol, respectively) hepatic damage in rats (Karthikeyan & Deepa Citation2010; Singh et al. Citation2011).

Two species, P. mucronata Roxb. (Patel et al., Citation2012; Savsani et al., Citation2014) and P. serratifolia (Rajendran & Saleem Citation2008), are reported to have cardioprotective activity towards a myocardial infarction rat model. The extracts provided protection to the heart via several mechanisms, i.e., (i) decreasing injured cardiac marker enzymes; blood glucose; heart tissue protein; and heart tissue nucleic acids; as well as (ii) maintaining the electrocardiogram (ECG) pattern and hemodynamics changes, increasing myocardial glycogen and restoring antioxidant status. Further investigation has ruled out cardiac stimulant activities of P. serratifolia extracts by significantly supporting positive inotropic and negative chronotropic actions similar to that of β-adrenergic effect, decreasing membrane Na+K+ATPase and Mg2+ATPase and increasing Ca2+ATPase (Rajendran et al. Citation2008). There was only one study reporting the gastroprotective activity of P. serratifolia leaves on aspirin-induced ulcer rats (Jothi et al. Citation2010). The evaluation was carried out at doses of 200 and 400 mg/kg by looking at several parameters: lesion index, total- and free-acidity, and percentage of ulceration. The findings suggested that P. serratifolia exhibited significant antiulcer and anti-secretory activities in both applied doses.

Neuropharmacological acitivities

So far, two studies have evaluated the hypnotic and the neuropharmacological effects of Premna species on animal models. Devi et al. (Citation2003b) evaluated the effects of the methanol extract of P. tomentosa leaves as a central nervous system (CNS) depressant using potentiation of phenobarbitone-induced hypnotic and locomotor activities on rats. At doses of 400 and 500 mg/kg orally, the extract decreased the locomotor activity and moderately increased the sleeping time, that were comparable to CNS depressant, chlorpromazine (10 mg/kg, i.p) yet significantly different to CNS stimulant, ephedrine hydrochloride (10 mg/kg, i.p). A recent study also evaluated the effect of P. integrifolia bark on locomotor activity of the rats in the open field and hole-cross tests (Khatun et al. Citation2014). The findings suggested that P. integrifolia significantly affected locomotor activity of the rats at the doses of 250 and 500 mg/kg, orally on both methods, therefore, might act as CNS depressant.

Discussion

This review summarizes the phytochemical work of more than 19 species (24 species once the synonyms are considered) of Premna with more than 250 secondary metabolites have successfully been isolated and identified. It comprises a high number of diterpenes, iridoid glycosides and flavonoids (glycosides and glycones), followed by sesquiterpenes, lignans, phenylethanoids, megastigmanes, glyceroglycolipids and ceramides. Xanthones and alkaloids were rarely identified though a few studies reported their presence in this genus. Meanwhile essential oils were reported in seven species. The distribution of identified secondary metabolites within the genus Premna is shown in .

Although the Premna genus is rich in diterpenes and iridoid glycosides, they were not well distributed within the studies species. Diterpenes were abundant in three species such as P. mollissima, P. serratifolia, and P. tomentosa while iridoid glycosides were reported abundantly in P. serratifolia, P. subscandens and P. microphylla. On the contrary, flavonoids seem to be well distributed among 16 reported species despite of their low number in comparison to other groups. Only a few species such as P. serratifolia, P. microphylla, P. mollissima, P. fulva and P. subscandens, have been extensively studied for their secondary metabolites. Nonethless, a previous review (Taskova et al. Citation1997) endorsed terpenoids, iridoids, and flavonoids to be used as taxonomic markers in the family Lamiaceae based on their occurrence in 39 species of 25 genera such as Sideritis, Stachys, Lamium, Phlomis, Ballota, Salvia, Ajuga, Teucrium. Thus, diterpenoids (icetexane, abietane, labdane, pimarane types), iridoid glycosides (catalpol derivatives), and flavonoids (flavonols and flavones) can be very useful to characterize the taxonomic markers of the genus Premna (Taskova et al. Citation1997) and to provide the secondary metabolite fingerprint of each species through infrared (IR), thin layer chromatography (TLC), high performance liquid chromatography (HPLC), mass spectroscopy (MS), or nuclear magnetic resonance (NMR) analysis.

Some of the biological and pharmacological studies reported on the studied plants have suggested scientific evidence to justify the various plant uses in traditional medicine. However, adequate biological and pharmacological studies on most of the species in the genus Premna have not yet been performed because most, especially in in vivo studies, were carried out using their crude extracts (). For example, none of the bioactive molecules have been identified from the active antimalarial Premna species. Similarly, some Premna species showed potential in vivo antihyperlipidemic, cardioprotective, hepatoprotective, gastroprotective, and neuropharmacological activities which require further studies to determine the active compounds and possible mechanisms for a particular activity. While, numerous isolated compounds have been isolated and evaluated for related biological activites, they were limited to in vitro studies. No toxicological studies that have been carried out, although some species, such as P. serratifolia, have been used in Ayurvedic medicine for a long time.

Table 4. Summary of pharmacological activities of Premna species.

There was no effort to qualitatively and quantitatively analyze the extracts used. Standardization of the extracts should be carried out to ensure consistency of the quantitative amounts of the active chemical markers in the plants of similar species collected from different locations. The variety and distribution of active secondary metabolites from this genus are useful as bioactive chemical markers for standardization and quality control purposes. Otherwise the work on biological activities may not be reproducible due to variations in the quantitative amounts of chemical constituents in the plants. These quantitative and qualitative differences in the chemical composition are related to responses of the plants to environmental factors or genetic adaptation of the populations growing at different altitudes to a specific environment (World Health Organization [WHO] Citation2000, Citation2003).

Conclusions and future prospects

Further investigations are required to transform the experience-based claims on the traditional uses of Premna species into evidence-based information. The present knowledge obtained mainly from experimental studies was critically assessed to provide evidence and justification for their traditional uses to propose future research prospects for this plant. Phytochemical studies on Premna species have led to characterization of diterpenoids, iridoid glycosides, and flavonoids as the charactetistic chemical composition of the genus. The in vitro and in vivo evaluation of biological properties of the extracts and isolates from various species of Premna on antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, cytotoxic, antihyperglycaemic, and other activities should lead to further detailed investigations to identify the bioactive compounds and their mechanisms of action. The antimalarial, hepatoprotective, cardioprotective and gastroprotective effects of the plant extracts should encourage further studies on these plants for use as preventive agents. Toxicological evaluation should be conducted to address any adverse side effects which may occur. The roles and mechanisms of the bioactive compounds should be addressed appropriately to understand the contribution of individual compound to the activities as well as to become potential lead molecules for development into drug candidates. Attempts should be made to carry out more preclinical studies of the standardized extracts and bioactive compounds of Premna species, which include determination of modes or mechanisms of action in different animal models, bioavailability, pharmacokinetics and toxicological studies before submission of potential candidates to serious randomized human trials is possible. As more scientific evidences on therapeutic effects are discovered, Premna species will be recognized as a valuable source of drug leads and pharmaceuticals.

Disclosure statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Funding

The authors greatly thank the Universiti Kebangsaan Malaysia for the financial support (grant no. DIP-2015-013) and the Zamalah Research Fellowship Scheme.

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