Role of traditional herbal medicine in the treatment of malaria

Virender Kumar , Vandana Garg ＊, Harish Dureja ＊

1Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana 124001, India.

Abstract

Malaria is one of the world's major public health concerns and numerous medicinal plants are commonly used for treating malaria. Traditional health care uses medicinal plants widely, but no scientific documentation is available and, there is a growing risk of losing this knowledge. Thus, this study aims to document the traditional use of medicinal plants in treating malaria and related conditions. In this review, numerous herbal medicines for antimalarial potential are explained. The literature survey was done using keywords i.e., malaria, herbal, herbal, traditional use, antimalarial,quinine, artemisinin, and traditional medicine by using PubMed, Science Direct, Google Scholar, and HINARI database. This review discusses the life cycle of the malarial parasite, what makes you attractive to mosquitoes, and the role of traditional herbal medicine in malaria.

Keywords Artemisinin; Antimalarial; Herbal; Malaria; Quinine

Highlights

The article provides a list of medicinal plants that are believed to be useful in the treatment of malaria.

The role of Quinine, Chloroquine, Artemisinin,Acanthospermum hispidum,Byrsocarpus coccineus,Carpolobia lutea,Dialium guineense,Heliotropium indicum,Keetia leucantha,Pupalia lappacea,Sansevieria liberica,Strychnos spinosaand Ananas comosus has been described in treatment of malaria.

Introduction

Malaria is one of the most vulnerable, widespread, life-threatening infectious diseases that cause millions of deaths across the globe [1]. The disease malaria not only affects the population in an area, but also disposes significant loss to the national economy and financial condition Malaria is considered a threat to a country's socioeconomic development, as it affects children's schooling with the disease and destroys the productive days of employees for work. The recorded number of people suffering from malaria cases was 241 million in 2020, as per the WHO report, and that too, maximum from Africa itself [2]. According to one report estimation, it has been stated that there will be a fall in the growth of GDP by 0.41% if there is a rise in the morbidity rate of malaria by 1% [3]. Charles Louis Alphonse Laveran first diagnosed the malarial parasites (plasmodium), a French army surgeon, from a patient's blood sample in 1907; he received a Nobel prize[4]. The literal meaning of malaria is “bad air” derived from medieval Italian words [5].

In humans, mainly four types of plasmodium species are known to cause malaria viz [6].

● Plasmodium falciparum

● Plasmodium vivax

● Plasmodium ovale

● Plasmodium malariae

These belong to theApicomplexaphylum,plasmodiumgenus, are strict intracellular protozoan (plasmodium) parasites [7]. The parasite mainly propagates in the stagnant water of ditches, ponds, etc., as they easily lay eggs and develops into larvae afterward. The life cycle of the malarial parasite is very versatile, as it depends upon two hosts viz. female anopheles mosquito (also the vector of the same disease) and human being. Out of these, an infection caused byPlasmodium falciparumis fatal. Various reports state a close relationship exists between humans and African apes’ malarial parasites [8]. In India, the most cases of malaria were found in Odisha, Chhattisgarh, Jharkhand, Meghalaya and Madhya Pradesh [9]. There are four main problems for managing malaria in a population viz [10].

● Development of resistance in malarial parasites sooner for easily affordable,safest, effective, and first-line drugs like Chloroquine.

● Mosquitoes which are vectors for this disease, are also getting resistant to various insecticides used to control them.

● Introduction of fake antimalarial drugs in the market, for example,artesunate blister packs for malaria management contained no active ingredient in the samples obtained from mainland south-east Asia [11].

● Lack of infrastructure and resources for managing malaria and its control in developing and underdeveloped countries.

As per WHO, two approaches [2] are used for controlling, treating and preventing malarial infection which are:

● Prevention: reduction in human-vector contact and lifespan of mosquitoes by using insecticidal nets, indoor residual spraying and administration of entire course of antimalarial drugs in the population at high risk in due course of time.

● Case management: treatment of affected individuals with chemotherapy(currently, ACTs are used, which are artemisinin-based combination therapies).

However, many chemical drugs have been developed to treat malaria patients.They were adequate for a more extended period, but slowly, the parasite developed resistance against them which posed a challenging task for treating malaria. Since the parasite life cycle is dependent on two hosts, so, with such a versatile life cycle and the continuous alteration in metabolic pathways in the parasite during its life cycle make it more cumbersome and arduous task for scientists to develop a vaccine against the malarial parasite. Due to this, no vaccine has been created, so it isn't easy to control its spread. So, this is high time to scrutinize and develop newer drugs that can tackle this major problem of drug resistance and helps in curing malaria [12].

Malaria patients are advised to follow a nutritionally balanced diet that includes cereals, pulses, vegetables, fruits, milk, milk products, fish, chicken soups/stews,sugar, honey, etc. that provides adequate nutrition and maintains fluid balance [13].

Since nature is full of enormous surprising things about the maximum of which human beings are unaware [14]. Hence, a shift has occurred for searching herbal plants with certain compounds as their secondary metabolites, potent enough against the malarial parasite and can help cure patients of malaria. This led to the evolution of a newer branch of science i.e., ethnopharmacology, which aims to find out those plant-based products rationally which were traditionally used for the treatment of malaria and were more prevalent in a local tribal community based on cultural values. This focuses on finding out those plant species have medicinal value and using them as a template for synthesizing newer drugs that are more effective [15]. Pineapple is one of the most consumed members of the family Bromeliaceae growing in several tropical and subtropical countries [16]. It contains substantial amounts of bioactive compounds, minerals, dietary fiber,nutrients, and enzymes. Bromelain is the proteolytic enzyme derived from the stem portion of the pineapple and showed various antiedematous, antiinflammatory fibrinolytic, anti-inflammatory and antimalarial activity [17]. In this review, we summarized the antimalarial effect of pineapple from the previous studies and proposed it as an herbal drug for treating malaria. Further, pineapple and bioactive compounds can be designed as a novel drug delivery system to deliver the drug efficiently and prevent resistance. The life cycle of the malarial parasite is very versatile as it depends upon two hosts, viz. female Anopheles mosquito (also the vector of the same disease) and the human being. First, the female anopheles mosquito bites a healthy human being to suck blood and accidentally delivers sporozoites into the human body. From this point onwards,the malarial infection gets initiated and propagates further. After that, the sporozoites infect the liver by migrating and invading hepatocytes, where they undergo schizogony (exo-erythrocytic schizogony) and form schizonts. The moment the hepatocyte ruptures, merozoites are released outwards and enter the bloodstream, infecting normal erythrocytes and invading after that. In some species likeP. vivaxandP. ovalea dormant stage (hypnozoites) can persist in the liver and cause infection relapse by invading the bloodstream even weeks or years later. To complete the life cycle, the malarial parasite must invade the host’s erythrocytes [18]. They again undergo schizogony or asexual multiplication(erythrocytic schizogony) in a similar way as in hepatocytes. In this way, it produces around 8-32 merozoites. Generally, four factors are responsible for controlling and governing the entry of merozoite into the RBCs, which are mentioned below [19]:

● Host cell- merozoite interaction.

● Reorientation of merozoite to expose apical prominence which, aids in contact with the host cell surface.

● Irreversible attachment between merozoite’s apical dominance and host cell surface followed by the formation of an electron-dense junction.

● Formation of parasitophorous vacuole due to invagination of the parasite into host cell.

HRP-1, EMP-1, HRP-2 and EMP-2 are the four major proteins, which are found expressed on infected RBCs [20]. Some of them get differentiated into sexual gametocytes (blood-stage parasites). Whenever at any moment, the erythrocyte ruptures, it gets released outside and starts infecting other surrounding normal erythrocytes as well, hence, creating a vicious cycle responsible for clinical manifestations of the disease. When a female anopheles’ mosquito again bites the infected individual, the male (microgametocytes) and female (macrogametocytes)gametes are ingested along with the blood meal, and the sporogonic cycle(Multiplication of malarial parasite in the mosquito body) commences. Soon, the microgametes fuse with the macrogametes in the mosquito’s stomach leading to the formation of zygotes which in turn, later becomes elongated and motile(ookinetes). They further develop into oocytes while invading the midgut wall.These grow and mature into sporozoites and get released on rupture. Additionally,they migrate toward the mosquito's salivary glands, where they are stored.Whenever the mosquito bites another healthy individual to suck blood meal, in turn, it transmits these stored sporozoites into that person's body, infecting him with malaria and this cycle continues further [21]. The Malaria Asexual Reproduction Cycle is shown in Figure 1 and gametocyte development is shown in Figure 2.

Figure 1 Malaria Asexual Reproduction Cycle [22]

Figure 2 P. falciparum Gametocyte Development [22]

What makes you attractive to mosquitoes?

Research in the past has shown mosquitoes to be selective predators. Much research has been done on what makes mosquitoes attracted to their prey, from genetic factors such as blood group to characteristics such as clothing color and body temperature.. The most important factor that attracts mosquitoes to humans is the scent of our bodies, but the smell of our bodies is influenced at least in part by our genes [23]. The carbon dioxide we exhale is highly attractive to mosquitoes,and it has been noticed that adults are more likely to get bitten by, mosquitos than children because of the larger amount of carbon dioxide they exhale.

These mosquitoes have thermosensors that can detect the heat of the body.Pregnant women's increased body temperature and carbon dioxide production make them more attractive to mosquitoes. What makes you attractive to mosquitoes is shown in Figure 3.

Figure 3 What makes you attractive to mosquitoes? [24]

Traditional medicine used for the treatment of malaria:

Quinine

Quinine is obtained from the cinchona tree. It was first discovered in the 17th century and used to treat malaria. It was also called Sacred bark, Jesuit’s, and Cardinal bark [25]. The food vacuole gets swelled by quinine which leads to the lysis of the cell by an increase in the granularity of the cell [26]. On the other hand,this traditional medicine did not gain resistance quickly to the parasite. Cinchona has been used as a medicine since the 1600s, and various studies have been conducted on the cinchona to study its medicinal properties. It has been used as a medicine for a long time. This medicine has shown favorable effects in the treatment of malaria till now.

Chloroquine

This traditional medicine causes a toxic effect on the parasite and results in the death of the malarial parasite. It acts by inhibiting the detoxification of hematin in the parasite's digestive vacuole [27]. The resistance to chloroquine in malarial parasite is mainly due to mutation at position 76 (K76T) in PfCRT (Plasmodium falciparumchloroquine resistance) [28]. Chloroquine is a doc for malaria due to its low toxicity to the host, cost-effectiveness, ease of use, and best clinical efficacy.However, the parasite has gained resistance due to its heavy usage 29]. The combination of the pyrimethamine-sulfadoxine act on Dihydropteroate synthase& Dihydrofolate reductase.

Artemisinin

Artemisinin is obtained from the sweet herb wormwood and used as a first -line treatment forPlasmodium falciparum. It is a widely used anti-malarial drug [30].The chemical structure responsible for the anti-malarial activity is tetracyclic 1,2,4-trioxane. Several studies show that it also contains anti-cancer properties[31]. The resistance is caused mainly due to mutation in the Kelch protein, present on the chromosome 13. The mechanism of action is now specified, but it acts in two ways. Firstly, by direct attack on mitochondria and interacts with Fe of hemoglobin which leads to the synthesis of ROS and attacks the protein of parasites [32]. This herbal medicine is used as anti-malarial as well as anti-cancer.

Acanthospermum hispidum

Various experimental studies have been conducted on theAcanthospermum hispidum. A study showed that it contains an anti-plasmodial property on W2 &3D7 strain (IC = 4.8 g/mL & 7.5 g/mL) [33]. These values are in the limit for the anti-malarial activity (IC 50 ～ 10 g/mL); this extract showed moderate cytotoxicity(IC 50 > IC 30 g/mL) on two cell lines. This plant also contains sesquiterpene lactones of the germacranolide group [34]. The molecules obtained from the Asteraceae have the most substantial anti-malarial properties.Byrsocarpus coccineus

Clinical studies have been conducted on theByrsocarpus coccineusto study anti-malarial properties.The extract ofThonn&Byrsocarpus coccineusdoes not show good anti-malarial properties . The methanolic and dichloromethane extract showed moderate activity (IC50= 54.7 & 41.6 g/mL respectively). It also contains tannins, glycosides, sugars, alkaloids and saponins. Anti-inflammatory properties have also been shown by theByrsocarpus coccineus, which helps treat malaria[35].

Carpolobia lutea

This traditional medicine shows various properties like anti-diarrheal, anti-ulcer and anti-malarial. The lipophilic extract ofCarpolobia lutea, showed a more favorable effect on W2 strain (IC50= 8.1 g/mL) than on 3D7 strain (IC50= 19.4 g/mL) [36]. It consists of phytoconstituents like triterpenic saponins (roots),tannins, anthraquinones, cardiotonic glycosides and alkaloids. This was the first time the plants were used as anti-malarial agents, further the researcher's attack towards herbal agents. A clinical study on mice showed that a 2450 mg/kg dose was safe for traditional use [37].

Dialium guineense

Only the dichloromethane extract ofDialium guineenseshowed moderate activity on the malarial parasite. The aqueous extract showed low activity (IC50= 65.5 g/mL) compared to the dichloromethane extract (IC50= 42.1 g/mL). A study showed that the molluscicidal activity of leaves & fruits was due to triterpenoid glycosides [38].

Heliotropium indicum

This traditional herb is used to treat symptoms of malaria, such as colics or hyperthermia. So, it can be used as an adjuvant in malaria medicine. It also shows anti-leukemic, ganglion-blocking, and anti-tumor activity. It doesn't show significant anti-plasmodial activity [39].

Keetia leucantha

The dichloromethane extract of twigs and leaves showed good anti-plasmodial activity, mainly chloroquine-sensitive strain (IC50= 11.3 & 13.8 g/mL resp. on 3D7 and IC50= 15.8 & 26.5 g/mL resp. on W2). The selectivity index of twigs &leaves was found to be 8.8 & 4.8, respectively [40]. The anti-plasmodial activity was shown by the aerial part of theKeetia leucanthasame as Canthium species(Rubiaceae), which was used as a traditional medicine for the treatment of malaria.

Pupalia lappacea

Pupalia lappaceadoes not show anti-plasmodial activity except for the dichloromethane extract, indicating moderate activity (IC50= 50.29 g/mL).Traditionally, it was used for different purposes like vomiting, abdominal colic,and cephalgia, which were malaria symptoms. Then, further, it was investigated for treating malarial symptoms [41].

Sansevieria liberica

First ever used herb for the study of anti-plasmodial activity in-vitro. The dichloromethane extract ofSansevieria libericaleaves showed moderate activity(IC50= 44.5 g/mL), but its selectivity index was very low. The twigs and leaves of theSansevieria guineensis(L.) Willd. from Guatemala showed antiplasmodial activity [42].

Strychnos spinosa

Strychnos spinosaconsists of alkaloids that were used as anti-plasmodial agents.The dichloromethane extract of leaves showed high antiplasmodial activity (IC50= 15.6 and 8.9 on 3D7 and W2, respectively). It has a higher selectivity index than 6.4. A study showed that the stem and bark showed low or no activity. This is the first time when the leaves ofStrychnos spinosawere used for the in-vitro study[43].

Other herbal parts or fruits in malaria

Modern antimalarial drugs are made from two subgroups of traditional medicines(artemisinin and quinines), both of which have been used for thousands of years to treat malaria. Traditional medicine is an important and sustainable source of treatment in areas where drug resistance levels are increasing, and access to effective antimalarial drugs is difficult [44]. The traditional belief is thatA.comosushas important antimalarial properties and often contains abundant polyunsaturated fatty acids (linoleic acid). Phillip et al. evaluatedin vivoantimalarial effect of the fruit peel ofA. comosus. In this study, using methanol as the extraction solvent, the fruit peel of the plant was fractionated with successive amounts of n-hexane, dichloromethane, ethyl acetate, methanol, and water. A curative antimalarial model using artemisinin combination therapy (ACT) as a reference drug was performed on mice infected withPlasmodium bergheiand treated orally 9 with three doses of the plant extract and one dose of each of its fractions and subtractions. Extracts from the plant exhibited significant non-dose dependent parasite inhibition (P< 0.001) between 44.84 and 76.09 %. The dichloromethane fraction showed the highest inhibitory effect (87.58%) among all fractions. Significant inhibitory effects were observed for the subtractions in the 84.14 to 92.54 % ranges. The inhibitory effect of ACT was found to be substantial,i.e., 83.92%. Hence, its strong antimalarial properties support the folkloric use ofA.comosusfor malaria treatment [45]. In another study, Abayomi et al.investigated the antimalarial effect of methanol -extractedA. comosuspeel extract(PEAC). They administered the extract at a dose of (100, 200, and 400 mg/kg) in mice using Peter's 4-day suppressive test. Biological progression of infection in mice infected with 1 X 106parasitized red blood cells. Parasite levels in the animals steadily increased throughout the course of the 14-day experiment. PEAC did not differ significantly from the untreated control group for infected individuals and the treated group for infected individuals. Mice t infected withP.beigheiand treated with chloroquine and artemether-lumefantrine did not show signs of parasitemia. The PEAC (400 mg/kg) prolongs the survival of mice by almost 20% by day 21, but the chloroquine extends it by nearly 80% by day 28.The survival rate of artemether-lumefantrine was 100% on day 28 [24]. Among the aryl amino alcohols, quinine is an alkaloid present in cinchona. Different preparations exist, including hydrochlorides, dihydrochlorides, sulphates,bisulphates, and gluconates; dihydrochloride is the most commonly used preparation. In intra-erythrocytic malaria parasites, quinine has schizonticidal properties. Age, pregnancy, immunity, and disease severity affect quinine pharmacokinetic properties and therapeutic responses [46]. Plasmodium falciparum infections are rapidly controlled with artemisinin and derivatives(collectively known as ARTs). The effectiveness of ART combination therapy is highly dependent on the rapid reduction of parasite burden. In addition to killing parasites through protein damage, dihydroartemisinin (DHA) also compromises parasite proteasome activity [47]. The use of artemisinin has been associated with reduced malaria transmission because they are active against gametocytes, the parasite form transmitted by mosquitoes [48,49]. But resistance to the existing drug therapy has been reported. As a result, there is a great need for novel antimalarials, especially those derived from medicinal plants. Pineapple and its bioactive compounds can be used in treating malaria, as suggested by the reported literature. I In many countries, pineapple is used as a folkloric treatment for malaria. Form ancient times, pineapple and related compounds were used in the treatment of malaria in comparison to the existing therapy.

Herbals drugs used in the treatment of malaria

Numerous herbal plants are used in the treatment of malaria. Some of the important plants with their metabolites, which are responsible for antimalarial effects are enumerated in Table 1.

Table 1 Herbal drugs used in the treatment of malaria

25 Diospyros quaesita Thwaites Ebenaceae Triterpene[76]26 Erythrina subumbrans Merr. Leguminosae Flavonoid derivatives [77]27 Garcinia polyantha Oliv. Clusiaceae Xanthone [78]28 Grewia bilamellata Gagnep. Tiliaceae Coumarinolignan [76]29 Guiera senegalensis J. F. Gmel. Combretaceae Naphthyl butenone [79]30 Harungana madagascariensis Poir. Clusiaceae Triterpene [80]31 Heimia salicifolia Link & Otto Lythraceae Alkaloid [58]32 Holarrhena antidysentrica Apocynaceae Norconessine, isoconessine [81]33 Hyptis suaveolens (L.) Poit. Lamiaceae Abietane-type diterpenoid endoperoxide [82]34 Mangifera indica Anacardiaceae Mangiferin, ambolic acid, ambonic acid, arabinan, mangiferonic acid [83]35 Mimosa pudica Fabaceae Mimosine, 2-hydroxymethylchroman-4-one [84]36 Ocimum sanctum Lamiaceae Eugenol, methyl eugenol, carvacrol [85]37 Papever somniferum Papaveraceae Morphine, codeine, papaverine [86]38 Parthenocissus tricuspidata Planch. Vitaceae Stilbene glycoside [87]39 Phyllanthus niruri L. Euphorbiaceae Coumarin [88]40 Piptadenia pervillei Vatke Leguminosae Phenolic derivatives Flavonoid derivatives [89]41 Polyalthia cerasoides (Roxb.) Bedd. Annonaceae Dimeric aporphine alkaloid [90]42 Polyalthia viridis Craib Annonaceae Quinone [58]43 Psorospermum glaberrimum Hochr. Clusiaceae Bianthrone [58]44 Punica granatum L. Lythraceae Tannins [88]45 Ricinus communis Euphorbiaceae Ricinoleic acid, ricinine, ferulic acid [91]46 Rourea minor (Gaertn.) Aubl. Connaraceae Lignan [92]47 Sarcococca hookeriana Baill. Buxaceae Steroidal alkaloids [93]48 Strychnos nuxvomica Loganiaceae Strychnine, brucine [94]49 Styrax benzoin Styracaceae Cinnamic acid, benzoic acid [94]50 Terminalia bellirica Combretaceae Ellagic acid, gallic acid [95]51 Vernoniopsis caudate (Drake) Humbert Asteraceae Helenanolide sesquiterpene lactones [96]52 Wedelia trilobata Hitchc. Asteraceae Sesquiterpene lactones [97]53 Zanthoxylum flavum Vahl. Rutaceae Coumarin [98]54 Zanthoxylum flavum Vahl. Rutaceae Tryptophane derivative [98]55 Zanthoxylum rhoifolium Lam. Rutaceae Alkaloid [98]56 Zingiber officinalis Zingiberaceae Gingerol, zingiberene [99]

Future perspective

Despite the increasing use of traditional medicine in treating malaria and the fact that it is usually more affordable and more readily accessible than Western medicine, it has limitations. The safety and efficacy of the drug are unknown, first of all. It also requires more work to pinpoint which plants, preparations, or dosages offer the best results, even among traditional healers. Several factors determine the concentration of active ingredients in a plant species. Despite these limitations,research can resolve all of them. Several systematic reviews, summarized here,have been published by the Research Initiative on Traditional Antimalarial Methods as well as guidelines to improve the quality of future research. Reviewing and updating these guidelines is still a long way to go. It is more appropriate to consider them as stepping stones for further research than as final products.

Conclusion

The world needs to control and eradicate malaria, which threatens humankind.Malaria has evolved into a complex multistage parasite in mosquitoes and their human hosts. To develop a malaria vaccine, one must thoroughly understand its biology. In traditional medicine, plants have remained an essential source of lead compounds, which have been used to develop drugs. Developing effective and promising combination treatments would provide an effective means of controlling malaria resistance, but to confirm the outcomes of the animal studies needed, further studies would need to be conducted using Plasmodium falciparum strains, as well as human volunteers.