Andrographis paniculata: A Review of its Phytochemistry and Pharmacological Activities

 

Ekta Singh Chauhan¹*, Kriti Sharma^{1, 2}, Renu Bist²

¹Department of Food Science and Nutrition, Banasthali Vidyapith, Rajasthan, India

²Department of Bioscience and Biotechnology, Banasthali Vidyapith, Rajasthan, India

 

ABSTRACT:

Andrographis paniculata is widely cultivated and its importance as a medicinal plant is growing up with stronger reports in support of its multifarious therapeutic uses. Taking great concern of the useful benefits of the plant, it can be advocated as a safe, highly important medicinal plant for mankind. This herb contains a large number of chemical constituents, mainly lactones, diterpenoids, diterpene glycosides, flavonoids and flavonoid glycosides. It has multiple pharmacological properties such as antibacterial, hepatoprotective activity, anti-cancer, antitumor, hypoglycemic, immunomodulatory and hypotensive activities. The earlier and current status of therapeutic usage, phytochemistry, pharmacological activity and toxicity profile research on Andrographis paniculata has been described in this review as to bridge the gap required for the coming research opportunities in future. It also emphasizes at compiling vast pharmacological applications to make the potential image of Andrographis paniculata as a multipurpose medicinal agent. The extracts and metabolites of this plant did not show any kind of significant acute toxicity in experimental animals.

 

 

 

INTRODUCTION:

Most of the world’s population especially in developing countries heavily depends on traditional physicians and therapeutic herbs to fulfill major healthcare requirements [1]. The association with conventional drugs leads to various problems. That is why many species of medicinal plants based on variations in their species and therapeutic potential have now been revalued by researchers. Therefore, there is a dire need to go through the previous literature published on some species to update the current status of knowledge is imperative. One of them is Andrographis paniculata (Acanthaceae). It comprises of about 40 species that has been used since ancient and ayurvedic times.

 

Andrographis paniculata is also known by the name of ‘King of Bitters’. It is an annual herb that grows up to a height of one meter.

It is inherent to India Srilanka and also distributed in different regions of Southeast Asia, China, America and West Indies. It grows well in almost all types of soil thus it is widely distributed. It has been cultivated due to its renowned therapeutic potential [2]. The aerial parts and roots of A. paniculata have been widely used in treating various maladies. It is known to be Mahatikta in (Sanskrit), Kiryato in (Gujarati), Mahatita in (Hindi) and Kalmegh in (Bengali) [3]. Various studies have been conducted by the researchers followed by the reports about therapeutic potential possessed by this herb. The phytochemical studies revealed that A. paniculata contains various compounds like diterpenoid lactones, flavonoids and miscellaneous compounds. Due to their presence, it possesses a wide range of pharmacological properties [4], [5]. This review presents the therapeutic potential, phytochemistry and pharmacological properties of A. paniculata (extracts and compounds) including antimicrobial, antiprotozoan, antiinflammatory, antioxidant, antidiabetic, antiinfective, immunostimulant, hepatorenal protective, sex hormone modulatory, liver enzymes modulatory, cytotoxic, insecticidal, neuroprotective, anticancer, antipyretic and anti-platelet activities. Furthermore, this review confers some toxicological aspects of A. paniculata.

 

Therapeutic Uses of Andrographis Paniculata:        

From centuries in Asia, the parts of Andrographis paniculata have been used as a traditional medicine in treating various ailments like stomachaches, inflammation, pyrexia and intermittent fevers. The whole plant of A. paniculata has been used as an antidote for snake-bite, poisonous stings of some insects. It is also used for the treatment of dyspepsia, influenza, dysentery, malaria and respiratory infections [6], [7], [8], [9]. The leaves extract of A. paniculata have been used as a traditional remedy in treating infections such as fever, colic pain, loss of appetite, irregular stools and diarrhea [10]. The decoctions of aerial parts were used to treat common cold, hypertension, diabetes, cancer and malaria [11]. Table 1 labels the therapeutic uses of different parts of A. paniculata.

 

Table 1.Therapeutic Uses of Different parts of Andrographis paniculata

S. No	Part	Therapeutic Uses
1.	Whole Plant	Poisonous sting treatment, dyspepsia, malaria and respiratory infections
2.	Aerial Part	Diabetes, hypertension, cancer and urinary tract infections
3.	Leaf	Fever, colic pain, mouth ulcers, hepatitis, tuberculosis and diarrhea
4.	Root	Febrifuge, tonic and anthelmintic

 

It has been used as a cold-property herb to get rid of the body heat and fever. It is also useful in dissipating toxins from the body [12]. In India, the tribals of Tamilnadu used this herb for a variety of ailments like dysmenorrhoea, leucorrhoea, pre-natal and post-natal care, malaria, jaundice, gonorrhea, wounds, cuts, boils and skin diseases [13], [14], [15]. The different usages of A. paniculata by these tribals are described in Table 2.

 

 

Table 2. Uses of Andrographis paniculata in folk medicine

S. No	Therapeutic Uses	Mode of Uses
1.	Malaria	20 g of whole plant is powdered, mixed in water, filtered and given internally twice a day
2.	Eczema	2 g of powder is given internally once a day for 40 days
3.	Jaundice	10 g of water extract of the herb, heat treated by dropping hot sonte, given 3 times a day for 6 days
4.	Gonorrhea	2 g of the powder given internally or Plant juice is applied on the wounds
5.	Infected wounds	Paste of herb mixed with turmeric applied externally

 

PHYTOCHEMISTRY:

A. paniculata shown to possess various compounds those are present in their aerial parts and roots which are commonly used in extracting its active principles. The factors like geographical region, harvest time and processing method describes the variability in its chemical content [16], [17]. The phytochemical studies of A. paniculata lead to isolation of various plant metabolites. The most important metabolites are terpenoids that accounts for a large proportion of its components and therapeutic properties. The other compound includes flavonoids (flavones), xanthones, polyphenols, macro and trace elements.

 

Main Bioactive Compounds in Andrographis Paniculata:

Terpenoids:

The diterpenoid lactones are the most common terpenoid compounds that are isolated from the aerial parts and roots A. paniculata (Table 3). The diterpenoids have been identified and isolated from A. paniculata. Andrographolide is most prominent in occurrence and quantity. It has a very bitter taste, colorless and crystalline in appearance [18]. It was first isolated in pure form by Gorter in 1911. The other diterpenoids that have been isolated mostly from the aerial parts of A. paniculata includes deoxyandrographolide and neoandrographolide. These diterpenoids (Table 3) have been isolated by several workers. Table 3 showed diterpenoids that are beside the dominant ones. Among these, unusual 23 carbon terpenoids isolated from the roots and aerial parts of the plant [19].

 

Table 3.Bioactive Compounds (Terpenes) present in Andrographis paniculata

S. No	Bioactive Compound	Type	Plant Part	References
1.	Andrographolide	Diterpenoid Lactone	Leaves	[20]
2.	Neoandrographolide	Diterpenoid Lactone	Leaves	[21]
3.	14- deoxyandrographolide	Diterpenoid Lactone	Aerial parts	[22]
4.	Andrographoside	Diterpene	Leaves	[23]
5.	14- deoxy 11, 12- didehydroandrographolide	Diterpenoid Lactone	Aerial parts	[24]
6.	19-O-β-D-glucopyranosyl-ent-labda-8(17), 13-dien-15, 16, 19-triol Ent-labdane	Diterpenoid Lactone	Aerial parts	[25]
7.	8α-methoxy-14-deoxy-17β- hydroxyandrographolide Ent-labdane	Diterpenoid Lactone	Aerial parts	[26]
8.	Andrographolactone	Diterpenoid Lactone	Aerial parts	[27]
9.	Andrograpanin	Diterpene	Leaves	[28]

Table 4. Flavonoids of A. paniculata

S. No	Compound	Type	Plant part	Reference
1.	5, 7, 2’, 3’-tetramethoxyflavone	Flavonone	Whole plant	[35]
2.	5-hydroxy-7, 2’, 3’-trimethoxy flavones	Flavone	Whole plant	[35]
3.	7-O-methylwogonin	Flavone	Root/aerial part/whole plant	[36], [37]
4.	Flavone-1, 2’methylether	Flavone	Root/aerial part/whole plant	[38]
5.	5-hydroxy-7, 8, 2’, 5’-tetramethoxyflavone	Flavonoids	Whole plant	[39]
6.	Dihydroskullcapflavone	Flavone	Whole plant	[40]

 

Flavonoids:

Flavones are known to be the major flavonoids that can be isolated from the aerial parts, roots and whole plant of A. paniculata (Table 4). 5, 7, 2’, 3’-tetramethoxyflavone is a type of flavonone found in whole plant. 5-hydroxy-7, 2’, 3’-trimethoxy flavones is a type of flavone found to be available in whole plant[29]. 7-O-methyldihydrowogonin is a type of flavone found in root and aerial part of the plant[30], [31]. Flavone-1, 2’methylether is a type of flavone found to be present in the root, aerial part and whole plant[32]. 5-hydroxy-7, 8, 2’, 5’-tetramethoxyflavone is a type of flavonoids found in whole plant[33]. Dihydroskull capflavone is a type of flavone found in whole plant[34].

 

Miscellaneous compounds:

Several miscellaneous compounds (Table 5) have been isolated, especially, from the roots of A. paniculata. Four xanthones were isolated from the roots using a combination of thin layer chromatography and column chromatography, and were characterized by infrared radiation, mass and nuclear magnetic resonance spectroscopic methods as 1, 8-dihydroxy-3,7-dimethoxy-xanthone, 4,8-dihydroxy 2,7-dimethoxy-xanthone, 1, 2-dihydroxy -6,8-dimethoxyxanthone and 3,7,8- trimethoxy-1-hydroxy-xanthone [41]. Five rare noriridoids designated as andrographolide A-E, along with curvifloruside were isolated from the roots of A. paniculate [42]. Arabinogalactan proteins were isolated from the dried herbs by Prajjal and his colleagues in 2007 [43]. Trace elements (Cr, Mn, Co, Ni, Zn, Cu, Se, Rb, Sr, and Pb) and macro-element (potassium and calcium) were identified and quantified in the roots [44]. Cinnamic acid, caffeic acid, ferulic acid and chlorogenic acid were also isolated from the whole plant [23], [35].

 

Table 5. Miscellaneous compounds of Andrographis paniculata

S.No	Compound	Type	Plant part	Reference
1.	Arabinogalactan	Protein	Herbs	Chaos and Lin (2010)
2.	1, 8-dihydroxy-3,7-dimethoxy-xanthone	Xanthone	Root	Dua et al (2004)
3.	Andrographidoid B	Noriridoid	Root	Xu et al (2012)
4.	Andrographidoid C	Noriridoid	Root	Xu et al (2012)

 

 

 

PHARMACOLOGY:

The use of the different parts of A. paniculata in folk medicine led the scientists to study its pharmacological properties as to authenticate this plant as a therapeutic agent. Many studies showed that this plant exhibited various biological activities such as antimicrobial, cytotoxicity, antiprotozoan, antiinflammatory, antioxidant, immunostimulant, antidiabetic, antiinfective, hepatorenal protective, sex hormone modulatory, liver enzymes modulatory, insecticidal, neuroprotective, anticancer, antipyretic, antiplatelet and toxicity [29], [45], [46].

 

Anti-microbial activity:

Aqueous extract, andrographolide and arabinogalactan proteins that were isolated from the dried herb of A. paniculata were screened for anti-microbial activity. The results showed that aqueous extract and arabinogalactan proteins possess antibacterial activity against Bacillus subtilis (B. subtilis), Escherichia coli (E.coli), Pseudomonas aeruginosa while andrographolide was the only one which is active against B. subtilis. All three were also reported to possess antifungal activity against Candida albicans [29]. The five rare noriridoides, andrographidoides (A-E) were screened for their anti-bacterial activity against E. coli, Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa and B. subtilis. None of the compounds showed inhibitory activity (MIC>100 µg/mL). Gentamycin, chloramphenicol and ciprofloxacin were used as positive controls [42].

 

Anti-inflammatory/Anti-allergic activity:

Aqueous extract when combined with methanol leaves extract showed significant alleviation of lipopolysaccharides that induced release of pro-inflammatory (NO, IL-1 β and IL-6), inflammatory (PGE2 and TXB2) and allergic mediators (LTB4). No inhibition was observed against histamine release (Chandrasekaran et al. 2010). Seven photochemicals, namely, andrographolide, neoandrographolide, isoandrographolide, andrograpanin, 7-O-methylwogonin, 14-deoxy-11,12- didehydroandrographolide and skullcapflavone (Figure 1) isolated from A. paniculata leaves were screened for in vitro anti-inflammatory and anti-allergic potential. The results showed that andrographolide, isoandrographolide, 7-Omethylwogonin and skullcapflavone-1 significantly inhibited inflammatory mediators NO and PGE2 release from lipopolysacharide (LPS) stimulated cultured macrophages. However, IL-1β production in LPS stimulated macrophages was inhibited by andrographolide, isoandrographolide and 7-O-methylwogonin. Also, IL-6 production from LPS induced macrophages was significantly (P<0.01) inhibited by andrographolide, isoandrographolide and skullcapflavone-1 in a concentration dependent manner. The results also showed that andrographolide, isoandrographolide and skullcapflavone-1 significantly suppressed TXB4 released in A23187 activated HL-60 promyelocytic leukemia cells. Furthermore, the anti-allergic properties of the phytoconstituents was investigated on A23187 induced LTB4 production. The result showed 30.5% and 19.6% inhibition of LTB4 production in A23187 induced HL-60 promyeolocytic leukemia cells at concentrations of 63 µM and 33.5 µM for skullcapflavone and 7-O-methylwogonin respectively. The IC₅₀ value for the reference standard captopril was 48 µmol/L. 7-O-methylwogonin was the only phytoconstituent that potently inhibited A23187 induced histamine release in RBL-2H3 rat basophil leukemic cells in a dose dependent manner[46]. Andrographolide, dehydroandrographolide and neoandrographolide isolated from the aerial parts of A. paniculata exhibited anti-inflammatory effects by interfering with COX enzyme activity. Andrographolide (30.1 µM) and dehydroandrographolide (28.5 µM) markedly inhibited COX-1 in ionophore A23187-induced human platelets. Dehydroandrographolide (28.5 µmol/L) and neoandrographolide (20.8 µM) strongly suppressed the LPS-stimulated COX-2 activity in human blood. In addition, dehydroandrographolide modulated the level of LPS-induced TNF-α, IL-6, IL-1β, and IL-10 secretion in human blood in a concentration dependent manner, showing that dehydroandrographolide has the highest efficacy. The result further showed that the mechanism of dehydroandrographolide may be related to down-expression of genes involved in the inflammatory cascade [47].

 

Andrograpanin (15-90 µM) isolated from the ethanol extract of the leaves inhibited NO and pro-inflammatory cytokines (TNFα, IL-6, IL-12p70) in a dose dependent manner from lipopolysaccharide activated macrophages. Significant (P<0.05) inhibition of NO was evident at a concentration of 30 µmol/L and at a concentration of 75 µM. Andrograpanin almost completely inhibited NO production. Significant inhibition of pro-inflammatory cytokines was evident at a concentration of 1.5µmol/L and there was an almost complete inhibition at a concentration of 90µmol/L. The RT-PCR and western blotting assays showed that andrograpanin inhibited productions of NO and pro-inflammatory cytokines through down-regulating iNOS and pro-inflammatory cytokines gene expression levels as well as p38 mitogen activator kinase signaling pathways. Further study showed that andrograpanin has more ability of down regulating IL-12 p35 and p40 proteins than their mRNA levels. This suggests that andrograpanin might be involved in down regulating the post-translation of IL-12 p35 and 40 proteins [48].

 

Antioxidant activity:

Andrographolide and aqueous extract of A. paniculata were screened for their antioxidant activity on nicotine induced oxidative stress in liver, kidney, heart, lungs and spleen of male wistar rats. The results showed that intraperitoneal administration of A. paniculata (25 mg/kg) and Aphanamixis polystachya (25 mg/kg) for a period of 7 days significantly (P<0.05) reduce levels of lipid peroxidation and increase antioxidant enzymes status in five organs screened as compared to nicotine [49]. The methanolic and aqueous leaves extracts of A. paniculata, andrographolide and 14-deoxy-11, 12-didehydroandrographolide exhibited lipid peroxidation inhibition in Srague Dawley rats and free radical scavenging activity against Diphenyl picrylhydrazyl (DPPH). The lipid peroxidation inhibition activity varied from 55.6% to 63.9% and 33.78% to 33.77% for methanolic and water extracts respectively. The activity of the methanolic extracts were higher and significantly different (P<0.05) from that of the water extract. The methanolic extract exhibited free radical scavenging activity ranging from 45.67% to 53.82%. The activity of andrographolide was 40.2% and for 12- didehydroandrographolide it was 46.43%. The water extract exhibited poor free radical scavenging activity ranging from 25.29% to 28.77%. The methanolic, water extracts and isolated compounds exhibited a lower free radical scavenging activity as compared to quercetin (89%) and butylated hydroxylanisole (71%) used as positive controls[50]. A fourteen-day oral treatment of Sprague Dawley rats with methanolic extract (1g/kg body weight) of dried leaves followed by carbon tetrachloride (CCl₄) challenge preserved antioxidant enzyme-catalase and superoxide dismutase activities in erythrocytes. Whereas, lipid peroxidation, alanine transaminase, aspartate transaminase and plasma thiobarbituric acid reactive substances were restored to values as compared to that who did not receive CCl₄. Andrographolide, 14-deoxy-11, 12- didehydroandrographolide were traceable in rat plasma followed by an oral dose of methanolic dried leaves extract (1 g/kg body weight) suggesting that these diterpenes may be responsible for the observed antioxidant activity [51].

 

Immunostimulant activity:

The ethanol extract of fresh plant and purified diterpenes like androgrpholide and neoandrographolide induced significant (P<0.01) stimulation of antibody and delay hypersensitivity response to sheep red blood cells in mice. The plant preparations also stimulate non-specific immune response of animals measured in terms of macrophage migration index, phagocytosis of C-leucine labeled E. coli and proliferation of splenic lymphocytes. The stimulation of both antigen specific and non-specific immune response was lower with andrographolide and neoandrographolide as with ethanol extract. This suggested that the substances present in the extract other than these diterpenes may play a role as immunostimulator [28]. The dichloromethane fraction of methanolic extract of whole plant significantly enhanced the human peripheral blood lymphocytes proliferation that is expressed as percentage stimulation index versus control increases by 52% at low concentrations. Whereas the methanolic extract, the petroleum ether fraction and aqueous fraction of methanolic extract cause 18%, 18% and 4% increase in human peripheral blood lymphocytes proliferation respectively suggesting that the immunostimulatory compounds of the methanolic extract are concentrated in the dichloromethane fraction. This observation led to the screening of three diterpenes like andrographolide, 14-deoxyandrographolide and 14-deoxy-11,12 didehydroandrographolide that are isolated from dichloromethane fraction. At a concentration of 1 µM, all the three compounds showed moderate increase in human peripheral blood lymphocytes proliferation with andrographolide which showed the highest proliferation with an increase of 14% [30].

 

Cytotoxicity:

The methanolic and petroleum ether extract, dichlomethane and aqueous fraction of methanol extract were screened for antiproliferative activity against HT-29 (colon cancer) cells. The methanolic extract inhibited the proliferation of HT-29 cells by an increase of 50% at a concentration of 10µg/ml. The petroleum ether and dichloromethane fractions inhibited proliferation of HT-29 cell with a GI₅₀ value of 46µg/mL and 10µg/mL respectively. The aqueous extract did not inhibit the proliferation of HT-29 cells. The diterpenes that were isolated from the dichlomethane fraction, andrographolide is the only one that inhibited proliferation of all cancer cells screened. Out of the entire cell screened, 14-deoxy-andrographolide showed moderate inhibition against the proliferation of two cancer cells. The diterpene 14-deoxy-11, 12-didehydroandrographolide did not inhibit the proliferation of any cancer cell line tested [30]. The findings are similar to the reports published earlier; they demonstrated the cytotoxic activity of andrographolide against human epidermoid carcinoma and lymphocytic leukemia cells [18]. The growth inhibitory activity of methanolic extract of aerial parts of A. paniculata and isolated compounds on mouse myeloid leukemia cells have also been reported [31]. The in vitro anticancer activity of andrographolide and its semisynthetic analogues-3 like 19-isopropylideneandrographolide, 14-acetyl-3,19-isopropylideneandrographolide and 14- acetylandrographolide were screened for their antitumor activity against MCF-7 human breast cancer and HCT-116 colon cancer cell lines. 19-isopropylideneandrographolide and 14-acetylandrographolide showed cytotoxicity against two cell lines tested. They were equally potent when compared to the parent andrographolide. In a similar study at the national cancer institute (USA); 19-isopropylideneandrographolide and 14- acetylandrographolide were screened and found to be cytotoxic against 60 human cancer cell lines [32]. Xanthones isolated from chloroform fraction of the roots were screened for cytotoxicity. The results showed that all the compounds having IC₅₀ values greater than 16µg/mL exhibiting non-cytotoxic behavior as per WHO criteria [42].

 

Antidiabetic activity:

Andrographolide and 14-deoxy- 11,12 - didehydroandrographolide isolated from the alcoholic extract of aerial parts of A. paniculata reduced the phenotypes indicating diabetic nephropathy in MES-13 cells. It includes secretion of extracellular matrix protein fibronectin, cytokine TGF-β, states of oxidative stress and apoptosis marker caspase-3. The compound 14-deoxy-11,12- didehydroandrographolide showed more potent activity than andrographolide in the reduction of apoptosis marker caspase-3, fibrosis marker cytokine TGF-β and plasminogen activator inhibitor-1. Both the compounds were shown to reduce reactive oxygen species in MES-13 cells [33].

 

The aqueous extract (50 mg/kg) of A. paniculata produced a significant (P<0.05) reduction (52.9%) in blood glucose level in streptozocin-induced hyperglycaemic rats. Freeze dried material of A. paniculata (6.25 mg/kg body weight) produced a more significant (P<0.01) reduction (61.81%) in blood glucose level. The results showed that the aqueous extract of A. paniculata did not produce significant reduction in the blood glucose level in normo glycemic rats [34].

 

Antiprotozoan activity:

Four xanthones were isolated from root fractions and screened for antiplasmodial activity against Plasmodium falciparum. Only a compound 1,2-dihydroxy-6,8-dimethoxyxantone possessed substantial antiplasmodial activity against Plasmodium falciparum with an IC₅₀ value of 4µg/ ml. This compound also exhibited in vivo antimalarial activity in mice infected with Plasmodium berghei where it produced substantial reduction (62%) in parasitemia [42]. This study involved the root fractions that showed higher antimalarial activity as compared to a previous study of fractions isolated from the leaves [52]. Andrographolide, neoandrographolide, deoxyandrographolide and andrographoside isolated from the leaves have been shown to possess some activity against Plasmodium berghei NK65 in Mastomys natalensis [53].

 

Insecticidal activity:

The ovicidal and larvicidal activity of the crude leaves extract of A. paniculata with five different solvents like benzene, hexane, ethylacetate, methanol and chloroform were tested against early third instar larvae of Culex quinquefasciatus (Say) and Aedes aegypti (Linn). The benzene, hexane, ethylacetate, methanol and chloroform extracts were found to be more effective against Culex quinquefasciatus than Aedes aegypti. The LC₅₀ values were 112.19, 137.48, 118.67, 102.05, 91.20 mg/L and 119.58, 146.34, 124.24, 110.12, 99.54 mg/L respectively. The methanol and ethyl acetate extracts were found to be most effective for ovicidal activity against the two mosquito species. The extract of methanol and ethylacetate also exerted 100% mortality at a concentration of 200mg/L against Culex quinquefasciatus and at 250 mg/L against Aedes aegypti [54].

 

Antiinfective activity:

The efficacy of the leaves extract of A. paniculata in the treatment of symptoms of uncomplicated upper respiratory tract infection has been reported. The findings obtained in a randomized double blind placebo controlled clinical evaluation using the visual analogue scale for quantification of symptoms. It showed that the Kalmcold treatment significantly (P<0.05) decreased all the symptoms score except for earache whereas symptoms remained unchanged or got worse after Day 3 for the placebo group. The study revealed that Kalmcold was 2.1 times or 52.7% more effective than placebo in reducing symptoms of uncomplicated upper respiratory tract infection [55]. A. paniculata extract SHA-10 (1200 mg/day) administered for a period of five days. It significantly (P<0.05) reduced the intensity of the symptoms (tiredness, sleeplessness, sore throat and nasal secretion) in uncomplicated common cold at the beginning of Day 2 treatment over placebo group. On Day 4, a significant decrease in the intensity of all the symptoms (headache, tiredness, ear ache, sleeplessness, sore throat, nasal secretion, phlegm, frequency and intensity of cough) was observed for A. paniculata group [56].

 

Hepatorenal protective activity:

Andrograholides and arabinogalactan proteins isolated from A. paniculata were screened for hepatorenal protective activity against ethanol-induced toxicity in mice. Intraperitoneal pretreatment of mice with andrograholide (500 mg/kg body weight of mice) and arabinogalactan (125 mg/kg body weight of mice) for 7 days before intraperitoneal injection of ethanol (7.5 mg/kg body weight) minimized the toxicity as revealed by different enzyme assays in liver and kidney tissues. Both andrograholide and arabinogalactan significantly (P<0.01) reduced level of glutamic-oxaloacetic transaminase, glutamic pyruvic transaminase, alkaline phosphatase and LP enzymes in liver and kidney in a comparable manner with reference standard Silymarin as compared to ethanol treated group [43].

 

Liver enzyme modulation:

Both andrographolide and 14-deoxy-11,12- didehydroandrographolide inhibited mRNA and protein expression of CYP1A2, CYP2D6, and CYP3A4 in HepG2 hepatoma cells. The lowest concentration (0.3 µm) of both diterpenoids produced more than 50% reduction in mRNA and protein expression of CYP3A4. This reduction was consistent with the enzyme activity. Both the compounds also reduced the ability of dexamethasone to induce CYP3A4 expression [57]. Andrographolide induced enhanced expression of CYP1 in PAH-responsive C57BL/6 male mice and did not alter CYP1 expression in PAH non-responsive DBA/2 male mice, ovariectomized females and orchiectomized male mice. However, the treatment with testosterone restored the effect of andrographolide on CYP1 in both orchiectomized males and ovariectomized females. This observation suggested a role for a male hormone system as a crucial mediator of modulation of CYP1 expression by andrographolide [58]. Andrographolide and A. paniculata extract significantly (P<0.05) increased the clearance and reduced the area under concentration time curve of theophylline (1 mg/kg) in blood of male Sprague Dawley rats. The elimination half-life and mean residence time of theophylline were shortened by 14% and 17%, respectively in the andrographolide treated rat in the presence of high dose theophylline (5 mg/kg). However, theophylline (5 mg/kg) accumulated in the blood of rats was pretreated with A. paniculata extract. This suggested that some herbal constituents present in A. paniculata extract may interact with theophylline and retard its elimination when administered at a high dose [59].

 

Sex hormone/function modulation:

Oral administration of the leaves extract in doses of 200, 600 and 2000 mg/kg body weight (i.e. 30, 90 and 300 fold higher than its daily therapeutic dose in humans) to pregnant rats for a period of 19 days for 200 mg/kg group and 11 days for 600 and 2000 mg/kg group respectively did not show any effect on the elevated levels of progesterone in the blood plasma of pregnant rats when compared with control groups. This suggests that A. paniculata at therapeutic doses cannot induce abortion [60]. Andrographolide (50 mg/ kg body weight) administered to male ICR mice significantly (P<0.05) decreased the mounting latency at 120 min and 180 min and increased the mounting frequency at 180 min after treatment. This suggested an improvement in sexual functions. The pre-incubation of endothelium-intact aortic strip with andrographolide for 10 min before adding nor-epinephrine resulted in a significant reduction in nor-epinephrine effect on aortic strip tension. An observation suggested that andrographolide improves sexual function by causing smooth muscle relaxation and increasing blood flow to the penis. Also, daily treatment of male mice with andrographolide (50 mg/kg) for 2, 4, 6 or 8 weeks significantly (P<0.05) increased serum testosterone levels on week 4 and this level declined back to normal (pretreatment levels) on week 6 and 8 with continued treatment. Moreover, andrographolide (50 mg/kg) was shown to have no significant effect on sperm count and motility [61].

 

Toxicity:

The safety of A. paniculata extract (Kalmcold) in genotoxic tests has been reported. In a study, the LD50 values has been determined to be higher than 5g/kg rats body weight in an oral acute toxicity [62]. Testicular toxicity was assessed by reproductive organ weight, testicular histology and ultra-structural analysis of leydig cells. The testosterone levels were not found after 60 days treatment with ethanol extract of dried herbs of A. paniculata in Sprague Dawley rats at doses of 20, 200 and 1000 mg/kg which suggested the relative safe toxicity profile [63], [64].

 

Neuroprotective:

The neuroprotective effects of andrographolide were studied on RSC96 cells in vitro. The RSC96 cell line consisting of immortalized rat Schwann cell line were treated with varying concentrations of andrographolide (0 to 50 μM), prior to the MTT assay. Cell proliferation, morphology, synthesis and nerve-specific gene expression were studied and andrographolide was found to be most effective between concentration range 0.78 and 12.5 μM. The treatment increased DNA content and promoted the gene expression of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, and the specific Schwann cell marker S100β (P,0.05). Andrographolide accelerated the proliferation of RSC96 cells without altering the Schwann cell phenotype [65]. In another study, andrographolide potently activated NF-E2-related factor 2 (Nrf2) and also upregulated heme oxygenase-1 (HO-1) expression in primary astrocytes. Andrographolide reduced Nrf2, ubiquitination efficiency, and turnover rate, followed by upregulation of Nrf2 mRNA between 8 and 24 h. HO-1 is a known gene target of transcription factor Nrf2, which is critically involved in cellular defense against oxidative stress [66]. Andrographolide recuperated the cognitive impairment in the social species Octodon degus (the only wild-type South American rodent that develops Alzheimer's-like pathology with age), a natural model of Alzheimer's disease. The treatment resulted in the recovery of spatial memory and learning performance, recovery of synaptic basal transmission, partial or complete protection of certain synaptic proteins and reduction of phosphorylated tau protein and amyloid beta aggregate maturation in aged degus [67]. In a similar study, andrographolide increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. It also stimulated neurogenesis increasing the number of newborn dentate granule neurons. The effect of andrographolide on APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease showed an increased cell proliferation and density of immature neurons in the dentate gyrus. Concomitantly the increase in neurogenesis, also induced activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice, evident by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis [68].

 

Cytotoxic and anti-tumor Activity:

The inhibition of hepatoma tumor growth induced by andrographolide (10 mg/kg) was found in a xenograft mouse tumor model in vivo. The miRNA chip analysis showed an increased expression of 22 miRNAs, whereas the expression of other 10 miRNAs decreased after treatment. Functional annotation of the target genes based on the differentially expressed miRNAs suggested that the majority of the genes were involved in a variety of signaling pathways, including miRNAs in cancer, mitogen-activated protein kinases (MAPKs) and focal adhesion [69]. Yang et al [70] studied the cytotoxic effect of andrographolide on human T-ALL (T-cell acute lymphoblastic leukemia) cells. It was found that 10 μg/mL compound could significantly induce Jurkat cells' apoptosis, depending on the inhibition of PI3K/ AKT pathway. Synergistic anticancer effects of andrographolide and paclitaxel (PTX) (widely used in chemotherapy for cancer treatment) were studied against A549 NSCLC (non-small cell lung cancer) cells. Andrographolide showed a time- and concentration- dependent inhibitory effect on highly proliferative MDA-MB-231 breast cancer cell proliferation, however, the treatment did not affect normal breast epithelial cells, MCF-10A (>80 %). Increased production of reactive oxygen species (ROS) with a corresponding decrease in mitochondrial membrane potential (MMP), externalization of phosphatidylserine was observed, while the population of apoptotic cells increased with prolonged exposure to andrographolide. Additionally, caspase-3 and caspase-9 were activated while Bax and Apaf-1 expression were significantly increased with a corresponding decrease in Bcl-2 and Bcl-xL expression in andrographolide-treated cells [71]. Furthermore, andrographolide was also reported to inhibit prostate cancer cells (LNCaP, C4-2b, and PC), by targeting cell cycle regulators, CXCR3 and CXCR7 chemokine receptors[72]. 14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid of AP, induced the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. The mechanism of action involved increase in cytosolic calcium concentration leading to a collapse in mitochondrial membrane potential in LC3-II cells. The ER stress pathway was significantly upregulated, DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor [73]. The inhibitory effects of andrographolide on the growth of multiple myelomas (MM) cells and its possible impact on the nuclear factor (NF)-κB signaling pathway were studied by Gao and Wang [74].

 

Antipyretic activity:

Antipyretic, analgesic properties of nilavembu kudineer chooranam: a classical preparation used in the treatment of chikungunya fever was reported by Anbarasu, et al [75]. Madav, et al [76] reported that andrographolide not showed any analgesic activity in hot plate test in mice while it showed significant (p < 0.05) analgesic activity in acetic acid-induced writhing in mice and Randall test in rats at 300 mg/kg dose. Authors also reported that andrographolide at 100 and 300 mg/kg, oral dose elicited significant (p < 0.05) antipyretic effect after 3 h of administration in Brewer’s yeast-induced pyrexia in rats and significant (p < 0.05) anti-ulcerogenic activity in aspirin induced ulceration in rats.

 

Antiplatelet activity:

Phytoconstituents and extracts of Andrographis paniculata was reported to exhibit anti-platelet activity by various mechanism of actions viz. decreasing platelet activating factor [77] and increasing eNOS-NO/cyclic-GMP pathway by decreasing PLC2-PKC and PI3 kinase/Akt-MAPKs [78]. Inhibitory effect of Andrographis paniculata extract and its active diterpenoids on platelet aggregation was studied by Thisoda, et al [79]. The results indicated that andrographolide and 14-deoxy-11,12-didehydroandrographolide significantly inhibited thrombin-induced platelet aggregation in a concentration and time-dependent manner while neoandrographolide had little or no activity. The results indicated that the standardized Andrographis paniculata extract may contain other anti-platelet compounds, which contribute to high anti-platelet activity. Amroyan, et al [80] tested andrographolide for PAF-induced platelet aggregation, where, andrographolide inhibited PAF-induced human blood platelet aggregation in a dose dependent manner (IC50 ~5 μM). These results indicated that andrographolide has a mechanism of action different from that of non-steroidal anti-inflammatory drugs (NSAID) and most likely associated with the cardiovascular and antithrombotic activity described of Andrographis paniculata. Wu, et al [81] isolated two new flavones designated as andropaniculosin A and ropaniculoside A and 30 known compounds from the whole plants of Andrographis paniculata.

 

Adverse effects:

An overdose of Andrographis paniculata extracts caused vomiting, gastric discomfort and loss of appetite that may be due to very high bitter taste of the herb [82]. Though this plant or its extract is safe, it is not to be taken during pregnancy as it is classified under class 2b in botanical safety hand book [83].

 

CONCLUSION:

A. paniculata has been extensively used as a traditional medicine. The diterpenoid lactones and flavonoids are the major phytochemical constituents present in the aerial parts of A. paniculata. The miscellaneous compounds like xanthones, rare noriridoids, macro and trace elements have been isolated from the roots. Various types of formulations, extracts and pure compounds have been obtained from this plant and shown to possess antimicrobial, antiinflammatory, antioxidant, antidiabetic, cytotoxicity, immune modulatory, sex hormone modulatory, liver enzyme modulatory, antimalarial, neuroprotective, anticancer, antipyretic, antiplatelet and hepatorenal protective activities. The diterpenoid lactones include the bitter compound andrographolide having most promising biological activities. This review provides comprehensive overview about the phytochemistry, therapeutic uses and pharmacology of A. paniculata. In addition, the clinical and laboratory studies on the toxicity of the plant extracts and other pure phytochemicals isolated are important to ensure its safety and eligibility as a source of modern medicine.

 

ACKNOWLEDGEMENT:

The authors sincerely express their gratitude to Banasthali Vidyapith and CURIE (DST-INDIA) for providing the necessary facilities for investigation.

 

CONFLICT OF INTERESTS:

Authors declare no conflict of interest.

 

 

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Accepted on 30.11.2018           © RJPT All right reserved

Research J. Pharm. and Tech 2019; 12(2):891-900.