Andrographis paniculata Usage in the Treatment of Viral Diseases

Received 14 Aug, 2021

Accepted 26 Dec, 2021

Published 01 Mar, 2022

Andrographis paniculata (A. paniculata) is a herbaceous plant used as a remedy for many diseases in traditional medicine. Numerous beneficial effects of A. paniculata have been demonstrated in multiple in vitro and in vivo studies, this study systematically reviews the relevant literature and provide a summary on the antiviral properties of A. paniculata in relieving viral diseases. This systematic review used the databases, Science Direct and PubMed for studies published from 1st of January, 1990 to 1st of May, 2021. To obtain further data, a manual search was also carried out on the bibliography of the referred articles. The following number of articles were identified in the literature search, Science direct = 167 and PubMed = 33. A total of 20 articles are included in this review. Andrographis paniculata has beneficial health effects in viral diseases such as Dengue, Chikungunya, Upper Respiratory Tract Infections (URTI), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). The wide range of medicinal effects observed from this plant is putatively from the phytochemicals andrographolide, neoandrographolide and andrographiside. The available evidence suggested that A. paniculatais a potential candidate to ameliorate multiple viral diseases, however randomized controlled clinical trials are needed to validate this hypothesis.

INTRODUCTION

Andrographis paniculata, a relatively common herbaceous plant¹ is present in the ethnopharmacopeia of many tropical nations. It is used to treat a variety of disorders as traditional medicine. Andrographis paniculata contains several secondary metabolites showing robust bioactivity in multiple disease models². The examined data from peer-reviewed studies focusing on the antiviral properties of andrographolide, a potent phytochemical of A. paniculata and its application in the treatment of viral diseases. Present data on its use in treating viral diseases and summarize the finding, focusing on the mechanisms of action. The data is reviewed to establish whether A. paniculata is done ameliorate multiple viral diseases and to establish a rationale for randomized controlled clinical trials towards establishing its efficacy.

Andrographis paniculata is an annual, 30-90 cm tall, erect herb, belonging to the Acanthaceae family, distributed throughout tropical Asian countries. It can be found in a variety of habitats such as plains, coastlines, hillsides and cultivated areas such as roadsides and farms¹. It is traditionally used as a medicinal

plant by different cultures around the world. The leaves are linear-lanceolate in shape with simple-opposite leaf arrangement while the stem is quadrilateral in shape (). All the parts of this plant such as leaves, seeds, fruits and flowers are used for medicinal purposes. The active phytochemicals in A. paniculata are andrographolide, neoandrographolide andrographiside, 14-deoxy-11,12-didehydroandrographolide, deoxyandrographolide and arabinoglycan proteins. Among them andrographolide, a diterpene lactone compound, is the principal active agent of this plant².

Many synonyms have been used in different languages to identify this plant including “Kaalmegha”, “Mahathikthaka”, “Heen bin kohomba”, “Shankhini”, “Neelavembu”, “Kirata”, “King of bitters”, etc³. In traditional medicine A. paniculata is considered a remedy for many digestive problems and skin diseases. Its medical actions are digestive, purgative, antipyretic and anthelmintic. It aids in the treatment of fever, worm infestations, skin diseases, liver diseases and digestive disorders⁴. Numerous beneficial health effects of A. paniculata have been identified in the ethnopharmacopea from different parts of the world as an antipyretic^5,6, anti-microbial, anti-inflammatory, anti-diabetic and in reducing the risk of cancer. This study aims to systematically review the scientific literature and to summarise the potential medicinal benefits of A. paniculata focusing on the treatment of viral diseases.

Methodology for data collection: A systematic review was carried out by using the published studies reporting on the anti-viral properties of A. paniculata, in viral diseases. A comprehensive systematic review was conducted by using the databases, PubMed and Science Direct for studies published from 1st of January, 1990 to 1st of May, 2021. The keywords used in this subject were Andrographis paniculata, medicinal properties, antiviral and viral diseases. Results were obtained only from the studies published in English while excluding commentaries and duplicate articles. The appropriate articles were selected and initially searched by reading the title and their abstracts. In this step articles that did not fulfil the requirements of inclusion criteria, were excluded. Thereafter, the remaining articles were screened by reading the complete text and synthesizing the data. Those articles which did not satisfactorily meet the inclusion criteria were excluded again. Additionally, relevant texts and internet sources were used for gathering the necessary information on A. paniculata. This research process was conducted independently and the articles which were to be included in the review was determined by an iterative consensus process at the final stage.

By using the above-mentioned criteria, the literature search identified these number of articles in the databases, respectively, Science Directs (n = 167), PubMed (n = 33). Two additional articles were selected manually by searching the bibliography of the selected articles for the inclusion criteria. After removing duplicate articles, the total number of articles included in the present review was 20 in Fig. 1.

Medicinal properties of Andrographis paniculata in viral diseases
Dengue fever: The previous study demonstrated that isolated andrographolide from A. paniculata possesses anti-dengue activity against the dengue-2 virus, by using in vitro and in silico methods. Their results suggested the inhibition of dengue viral replication resulting in a reduction in dengue viral infection⁷. The inhibition of Dengue Virus (DENV) infection of liver cells by andrographolide was tested using a proteomic based approach, with andrographolide demonstrated to possess antiviral activity⁸. Another study, tested the anti-dengue viral activity of bothethanolic and aqueous extract of A. paniculata, using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) method and SYBR green quantitative real-time Polymerase Chain Reaction (PCR) method and revealed that A. paniculata has anti-dengue viral effects and proposed the use of A. paniculata as a natural plant product to fight against Dengue fever⁹.

The anti-viral potential of andrographolide, derived from A. paniculata, against the Dengue virus, was evaluated, showing it may be used in the post-infection stage of the disease¹⁰. Here, the antiviral activity of andrographolide against Dengue Virus (DENV) serotype 2 was evaluated in two cell lines (HepG2 and HeLa) while the activity against DENV 4 was evaluated in one cell line (HepG2).

Fig. 1: Summarized search strategy of the review

The anti-dengue activity of andrographolide investigating the toxic effect of the compound andrographolide from A. paniculata leaf extract, against the dengue vector Aedes aegypti¹¹. The ability to inhibit the activity of Dengue Virus Serotype 1 (DENV-1) in in vitro assays of the methanol extracts of A. paniculata was demonstrated and suggested that it may be used as an alternative treatment or dengue¹².

Common cold and influenza: The anti-influenza activity of andrographolide, a secondary metabolite of A. paniculata was shown as a therapy for influenza A virus infection, using mice¹³. Significant antiviral activity against the Highly Pathogenic Avian Influenza (H5N1) virus was shown by using both water and ethanol extracts of A. paniculate¹⁴. The study revealed that the anti-inflammatory activities of didehydroandrographolide (DAP) another secondary metabolite of A. paniculata can be used as a curative agent against influenza A viruses (IAV)^15,16.

The antiviral activity of A. paniculata ethanol extract was shown to reduce the viral load in A549 cells infected with Simian Retro Virus (SRV) using RT-PCR analysis¹⁷. The results revealed that A. paniculata ethanol extract reduced the SRV virus titer due to its anti-viral activity. The antiviral activity of A. paniculata was demonstrated with andrographolide inhibit neuraminidase activity of H1N1 (swine flu) positive patients¹⁸.

A randomized, double-blind placebo-controlled clinical study was conducted to evaluate the efficacy of Kalm Cold, (an extract of A. paniculata), in patients with Upper Respiratory Tract Infection (URTI) and the study suggested that it was effective in reducing the symptoms of URTI¹⁹. Among plants tested for conditions associated with viral infection and inflammation, A. paniculata showed the highest inhibition of RANTES secretion by influenza A virus (H1N1) infected human bronchial epithelial cells (A5 49)²⁰.

Sharma et al.²¹ conducted a randomized double-blind placebo study to evaluate the effectiveness of A. paniculata SHA-10 extract in reducing symptoms and signs of common cold, demonstrating high effectiveness in reducing symptoms of influenza infection with no adverse effects.

The results showed that, in 2010, a randomized, double-blind placebo-controlled clinical study was conducted by ChiehKo et al.¹⁹, to evaluate the efficacy of an extract of A. paniculata and in the year 1999 also, a randomized double-blind placebo study has been conducted by Caceres et al.²¹, to evaluate the effectiveness of A. paniculata SHA-10 extract in reducing symptoms and signs of the common cold.

Chikungunya virus infection: Silver nanoparticles (AgNPs) biologically synthesized from A. paniculata, Phyllanthus niruri and Tinospora cordifolia and evaluated their antiviral properties against Chikungunya virus. The effectiveness of AgNPs of plants as antiviral was demonstrated and proposed as an alternative treatment against viral diseases²². A study was carried out by Shi et al.²³, to determine the potential of andrographolide as a treatment for Chikungunya viral (CHIKV) infection and demonstrated that andrographolide inhibited CHIKV replication and could therefore be an effective therapeutic agent against CHIKV.

SARS-CoV infection: The suppression of the main protease (M^pro) activities of 2019-nCoV and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), by both andrographolide and its fluorescent derivative, the nitrobenzoxadiazole-conjugated andrographolide (Andro-NBD), was demonstrated. Their results suggested that further extensive investigation of andrographolide on the suppression of 2019-nCoV is warranted²⁴.

The immune-protection and anti-viral response of A. paniculata against COVID-19 infection were analyzed by using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) metabolomics and combination synergy analysis based on network pharmacology. They concluded that, a synergy between andrographolide and other identified molecules, as safe and efficacious anti-inflammatory agents, of benefit to upper respiratory tract infections²².

HIV infection: A study was conducted by testing a series of synthesized andrographolide derivatives, evaluating them for anti-HIV activity in a virus infectivity assay using TZM-bl cells. The results showed andrographolide derivatives are promising candidates for the prevention of HIV infection²⁵.

Zika virus infection: Andrographolide derivatives with quinoline moiety, against Zika virus infection studied, where the andrographolide derivatives were shown to be protective against Zika infection. The potential for developing andrographolide derivatives with quinoline and related moieties against Zika and other arboviruses was shown²⁶. The results from the above studies are summarized in Table 1.

The available studies suggest that A. paniculata prevents cell infection and viral replications in the Zika virus HIV (Human Immunodeficiency Virus), Novel Coronavirus (2019-nCoV), Chikungunya virus, Influenza A virus (H1N1), Swine flu (H1N1) virus, Simian Retro Virus (SRV), A(H1N1) influenza virus, Avian influenza virus (H5N1), Influenza A Virus and Dengue virus in Fig. 2. The different parts of A. paniculata possess varying amounts of active secondary metabolites and this diversity of chemical constituents may underlie the wide range of medicinal effects as shown in traditional medicine, as rationalize for a spectrum of phytochemicals^27-29. Further elucidation of the mechanisms underlying these medicinal effects awaits further investigation. “andrographolide”, a bioactive phytochemical in A. paniculata has potent antiviral properties. However, the paucity of data from controlled clinical trials on the efficacy of A. paniculata as an effective treatment for human viral diseases, particularly as polyherbal preparations as used in traditional treatments, awaits further study.

Table 1:

Medical properties of A. paniculata in viral disease

Disease	Used material/compound	Viral category	Identified mechanisms/role	References
Dengue	Andrographolide	Dengue virus	Isolated the andrographolide from the A. paniculata by supercritical	Weerakoon et al.5
			fluid extraction technique and characterized the isolated compound
			along with with-it anti-dengue activity against DENV-2 in vitro
			and silico methods. Isolated compounds were capable of
			inhibiting dengue replication
	Andrographolide	Dengue virus	A total of 17 (1D) and 18 (2D) proteins were identified as differentially	Weerakoon et al.6
			regulated. The analyses identified proteins involved in chaperone
			activities, as well as energy production
	Both ethanolic and aqueous	Dengue virus	In vitro antiviral activity was performed against the dengue virus by the	Kaushik et al.7
	extracts of A. paniculata		3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
			method and SYBR green quantitative real-time polymerase chain
			reaction (PCR) method. Cytotoxicity was evaluated by MTT
	Andrographolide	Dengue virus	The antiviral activity of andrographolide against dengue virus (DENV)	Paemanee et al.8
			serotype 2 was evaluated in two cell lines (HepG2 and HeLa) while the
			activity against DENV 4 was evaluated in one cell line (HepG2)
	Leaf extract compound	Dengue virus	The toxic effect of the leaf extract compound andrographolide from	Ramalingam et al.9
	andrographolide		A. paniculata against the dengue vector
	Standardized methanolic extracts of	Dengue virus	The maximum non-toxic dose (MNTD) of the six medicinal plants	Panraksa et al.10
	A. paniculata, Citrus limon,		was determined by testing the methanolic extracts against
	Cymbopogon citratus, Momordica charantia, Ocimum sanctum and Pelargonium citrosum		Vero E6 cells in vitro
Common cold	Andrographolide	Influenza A virus	NF-κB and JAK-STAT signalling pathways were attenuated	Edwin et al.11
and Influenza			by andrographolide
	Crude extracts of A. paniculata, Curcuma longa,	Avian influenza	Both water and ethanol extracts of all the five plants showed	Tang et al.12
	Gynostemmapentaphyllum, Kaempferia parviflora and Psidium guajava were obtained by both water and ethanol extractions	virus (H5N1)	significant antiviral activity against the H5N1 virus
	14-Deoxy-11,12-didehydroandrographolide (DAP),	A(H1N1) influenza virus	14-Deoxy-11,12-didehydroandrographolide (DAP), with the non-toxic	Ding et al.13
	a major component of A. paniculata		concentration of 1000 mg/kg/day, effectively reduced the mortality
			and weight loss of mice lethally challenged with
			A/chicken/Hubei/327/2004 (H5N1) or A/PR/8/34 (H1N1)
			influenza A viruses (IAV) when initiated at 4 hrs before infection
	Ethanol extract of A. paniculata	Simian Retro Virus (SRV)	The antiviral activity of the extract was determined by observing	Sornpet et al.14
			its ability on inhibiting virus load in A549 cells transfected with
			Simian Retro Virus (SRV) by RT-PCR analysis
	Andrographolide	Swine flu (H1N1) virus	The potential of andrographolide to inhibit neuraminidase	Cai et al.15
			activity of H1N1
	An extract of A. paniculata	Common cold	Quantification of symptom scores by Visual Analogue Scale.	Churiyah et al.16
		viruses	Nine self-evaluated symptoms of cough, expectoration, nasal
			discharge, headache, fever, sore throat, earache, malaise/fatigue
			and sleep disturbance were scored
	Nine ethanol extracts of medicinal	Influenza A virus (H1N1)	Plants tested at the concentration of 200 μg mL–1 possessed	Seniya et al.17
	plants were screened for their effect	epithelial cells	more than 50% suppressing effect on RANTES secretion by
	on RANTES secretion		H1N1-infected A549 bronchial
	Dried extract of A. paniculata	Rhino virus	The effectiveness of A. paniculata SHA-10 extract in reducing the	Saxena et al.18
			prevalence and intensity of symptoms and signs of the common
			cold as compared with a placebo
Chikungunya	Biologically synthesized AgNPs from	Chikungunya virus	Biological synthesis of AgNPs from A. paniculata, Phyllanthus niruri	Ko et al.19
	A. paniculata, Phyllanthus niruri		and Tinospora cordifolia and evaluated their antiviral
	and Tinospora cordifolia		properties against chikungunya virus
	Andrographolide	Chikungunya virus	Andrographolide showed good inhibition of CHIKV infection and	Cáceres et al.20
			reduced virus production by approximately 3log10 with a 50%
			effective concentration (EC50) of 77 μM without cytotoxicity.
			Time-of-addition and RNA transfection studies showed that
			andrographolide affected CHIKV replication and it was shown
			to be cell-type independent
SARS-CoV	Andrographolide and its fluorescent derivative,	Novel coronavirus	Both andrographolide and its fluorescent derivative, the	Sharma et al.21
infection	the nitrobenzoxadiazole-conjugated	(2019-nCoV)	nitrobenzoxadiazole-conjugated andrographolide (Andro- NBD),
	andrographolide (Andro- NBD)		suppressed the main protease (Mpro) activities of 2019-nCoV and
			severe acute respiratory syndrome coronavirus
	Andrographolide	Novel coronavirus	The molecules from kalmegh provide immune-protection and anti-viral	Wintachai et al.22
		(2019-nCoV)	response via involving different pathways, like toll-like receptor pathway,
			PI3/AKT pathway and MAP kinase pathways against COVID-19 infection
HIV infection	A series of andrographolide derivatives	HIV (Human	Andrographolide and derivatives inhibited gp120-mediated cell fusion.	Shi et al.23
		Immunodeficiency Virus)	The computer-aided modelling revealed binding of these molecules
			to important residues of the V3 loop region of GP120 protein
Zika virus	Twenty-four analogues of	Zika virus	The rational and optimal combined modification/s at 3-, 14- or 19-positions	Banerjee et al.24
infection	14-aryloxy andrographolide		can make derivatives less toxic and more potent against Zika infection and
			both of 3 and 17bare suitable as leads for designing the new generation of
			andrographolide derivatives with quinoline or its structure- and
			property-related moieties against Zika virus and other arboviruses

Fig. 2: Andrographis paniculata showed antiviral effects on multiple viruses

CONCLUSION

The data from available studies suggested that A. paniculata has beneficial medicinal properties in amelioration of currently prevalent viral diseases. Therefore, this medicinal plant which features in the ethnopharmacopeia of multiple cultures is a strong candidate for use in antiviral therapies, rationalizing further clinical trials towards establishing its clinical efficacy.

SIGNIFICANCE STATEMENT

This study reveals that A. paniculate, a plant used in traditional medicinal treatment, shows efficacy in the treatment of several viral diseases. Further validation of A. paniculate-based treatments in controlled clinical trials on viral diseases is rationalized by this review.

ACKNOWLEDGMENTS

The authors are very thankful to the library staff of the Institute of Indigenous Medicine, the University of Colombo for their support given while using the databases.

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