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Plant-Based Alternative Treatment for Leishmaniasis: A Neglected Tropical Disease

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Nargis Shaheen, Chaitenya Verma and Naveeda Akhter Qureshi

Submitted: 01 August 2021 Reviewed: 09 December 2021 Published: 13 April 2022

DOI: 10.5772/intechopen.101958

From the Edited Volume

Leishmaniasis - General Aspects of a Stigmatized Disease

Edited by Leonardo de Azevedo Calderonon

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Leishmaniasis is a third most important vector born disease caused by intracellular parasite belongs to genus Leishmania. The leishmaniasis is prevalent in 102 countries/areas worldwide. Approximately, it effected 350 million people worldwide. Leishmaniasis effects developing and undeveloped countries globally. Antileishmanial drugs (pentavalent antimonials, stibogluconate, miltefosine, paramycin, and amphotericin) are most vital tool for curing leishmaniasis. However, none of these drugs is free from side effect including cost, toxicity, drug resistance, administration route, and prolong time, these disadvantages are main obstacle in the Leishmania infection eradication. Considering the increasing cases of leishmaniasis and drug resistance there is an urgent need for an effective and novel approach against leishmaniasis. Therefore, many researchers have tried to develop new medicines for the treatment of Leishmania infection. In the course of new therapies identification, plant based compounds were found to be an alternative that can be either used directly or with structural modifications. Several plants have been known for ages to be the source of phytochemicals with high values of medicines. These phytochemicals have been extracted by various techniques and have shown efficacy for the curing of several diseases. This chapter study explain various applications based on green approaches drugs for the treatment of leishmaniasis.


  • leishmaniasis
  • treatment
  • nanoparticles
  • alternative
  • green approach

1. Introduction

1.1 Leishmaniasis

The neglected tropical diseases (NTDs) are a group of about 17 parasitic diseases. The NTDs are prevalent in many tropical and subtropical countries that present the most common illness of the poorest people worldwide [1]. Leishmania infection constitutes a foremost public health issue with a rising burden over the last decade and is the second main cause of disease and death [2]. Leishmaniasis is prevalent in 102 countries/areas worldwide [3]. Leishmania infection affects approximately 1.5–2 million people, while 350 million are at risk of this pathogen [4, 5]. The causative agent of leishmaniasis is parasite protozoa of the genus Leishmania and is transferred via vector sandfly bite belongs to genus Lutzomyia and Phlebotomus [6].

Three clinical forms of leishmaniasis have been reported concerning parasite location in the infected tissues, that is, visceral leishmaniasis (VL) which is a less common type of leishmaniasis and it causes spleen and liver destruction and causes death if does not receive timely treatment; cutaneous leishmaniasis (CL), which affect only localized skin parts; and mucocutaneous leishmaniasis (MCL), which has the ability of mucus tissue destruction [7, 8]. About 0.7–1.2 million CL and 0.2–0.4 million VL cases are reported annually. Approximately CL cases (90%) are spread across three main areas, that is, (a) Syria, Afghanistan, Saudi Arabia, and Iran; (b) Tunisia and Algeria; and (c) Peru and Brazil [9, 10]. Annual visceral leishmaniasis (VL) cases are estimated to be less than 100,000, down from 400,000 in previous estimates [11], with more than 95% of cases reported to the World Health Organization (WHO) from Brazil, China, Ethiopia, India, Kenya, Nepal, Somalia, and Sudan. Currently, 54 Leishmania spp. are known and twenty-one are human’s pathogenic [8].


2. Therapeutic approaches and their limitations

Leishmaniasis is one of the most common NTDs, and it comes with a slew of negative and life-threatening consequences, including significant morbidity, early death, and long-term disability. Treatment entails limiting illness spread and utilizing existing criteria, but present medicines, such as chemical pharmaceuticals, need long-term treatment, minimal efficacy, and a slew of hazardous side effects. Only a few prevention strategies are available, despite the fact that no appropriate medications have been produced to prevent the virus, which is widely transmitted among the human population [12]. Some clinically approved medications are discovered among them to treat this endemic condition, that is, meglumine antimoniate (glucatime), sodium stibogluconate (pentostan), amphotericin B, and miltefosine. Excessive use of these chemotherapeutic sources, on the other hand, has been linked to antagonistic consequences [13]. As a result, researchers are looking for natural ways to treat leishmaniasis. Leishmaniasis treatment using chemical-based drugs various pharmacological medications, such as amphotericin B, pentamidine, miltefosine, and paromomycin, have been used in the treatment of leishmaniasis for numerous years. Due to the time-consuming method and high toxicity paired with significant adverse effects, none of the clinically approved medications could be considered as the ultimate source of treatment. Furthermore, the most commonly used medications do not completely eliminate parasites from all afflicted individuals [14]. The applications of several of these drugs, as well as their drawbacks, are explained further below. Pentavalent antimonials can be given via intravenous, intramuscular, and intralymphatic methods, with an optimum dose of 20 mg/kg/day (28–30 days) and a potentiality of 35–95%. This medicine can cause toxicity such as nephrotoxicity, hepatotoxicity, severe cardiotoxicity, and pancreatitis if used excessively [12, 13]. Miltefosine, when given orally, had an inhibitory effect on Leishmania growth but also had a negative effect, causing severe infection symptoms such as nephrotoxicity, teratogenicity, vomiting and diarrhea, and hepatotoxicity [15]. Paromomycin, which is also used to treat leishmaniasis, has been documented to have several hazardous side effects during treatment, including severe nephrotoxicity, hepatotoxicity, and ototoxicity [16]. Pentamidine, at a starting dose of 3 mg/kg/day, has the potential to slow Leishmania development while also causing significant side effects including as hypotension, hyperglycemia, tachycardia, pancreatic damage, and electrocardiographic abnormalities changes [14]. Existing chemotherapies have a number of drawbacks, including high cost, increased toxicity, and acquired resistance to parasitic strains, as well as other side effects during their prevention mechanism, prompting scientists and medical practitioners to develop a new therapeutic system to treat NTDs. Plant extracts, bioactive chemicals, and secondary metabolites obtained from specific plant species, as well as various types of NPs manufactured using plant extract, have become promising as well as safer preventative medicines in recent decades.


3. Natural methods

Plant-based conventional treatments have been employed in the treatment of infectious diseases since ancient times. Plant extracts and specific bioactive compounds isolated from plants are currently employed as either direct medicinal sources or as herbal medications to treat leishmaniasis and other microbiological infections [17]. Due to their nontoxic, environmentally friendly, and cost-effective features, medicinal plants become more favorable than other chemotherapies. Furthermore, natural chemicals derived from plants are regarded as a safe and effective treatment for leishmaniasis [18].

The root extract Bidens pilosa has been reported for antileishmanial potential against promastigotes of L. amazonensis with IC = 1.5 μg/ml). The Eugenia uniflora oil inhibit the growth of promastigotes and amastigotes of L. amazonensis while Ageratum conyzoides has been active against amastigots form of Labrus donovani [19]. The component of Casearia sylvestris and Melampodium divaricatum has been reported against L. amazonensis with IC50 = 10.7 and 14.0 μg/ml [20]. Furthermore, the active components 1,8-cineole, -pinene, and p-cymene from Protium altsonii and P. hebetatum (Burseraceae) showed dose-dependent amastigote inhibition, with IC50 values of 48.4, 37, and 46 g/ml, respectively [21]. The butanol fraction of K. odoratissima displayed antileishmanial activities against L. major promastigote and amastigote with an IC50 value of 154.1 g/ml [22].


4. Role of plant-based nanoparticles in leishmaniasis treatment

Infectious illness control methods have revolutionized translational sciences, allowing for the development of a better infectious disease control approach. Nanomedicine has showed tremendous promise in the development of very sensitive diagnostic tools with outstanding medication delivery properties. Nanoparticle-conjugated medications have recently been examined as a cost-effective, alternative therapy with improved efficacy. Toxicity, on the other hand, is a significant impediment that must be overcome. Several studies have demonstrated that several metal/metal oxide nanoparticles, as well as the Leishmania causative organism, have effective antibacterial effects due to their large surface area and unique characteristics. Nanoparticles made from crude and various solvent-fractionated extracts of medically significant plants are thought to be effective delivery for specific phytoconstituents into cells. Keeping in view the effective antimicrobial activities of silver metal, silver/silver oxide NPs synthesized using a variety of medicinally important plant species, including Mentha arvensis L., Ficus benghalensis, Cuminum cyminum, Moringa oleifera, Silybum marianum, and Sechium edule, at a dosage of 10, 300, 0.5, 246, and 51.88 μg/ml tested against L. tropica, L. donovani, L. major, and L. donovani, respectively [23, 24, 25, 26, 27]. This condition has also been reported to be prevented utilizing gold and silver bimetallic NPs produced from therapeutically significant plants [28]. However, Au-NPs derived from Cannabis sativa had excellent antileishmanial activity against amastigote forms (IC50: 171•00± 2•28 μg/ml) [25]. The flavonoid 7,8-dihydroxyflavone, which is common in plants used to make gold nanoparticles, has also been shown to prevent leishmaniasis [29]. The cytotoxicity of ZnO-NPs against L. tropica was likewise observed to be dose-dependent (IC50: 8.30 μg/ml). With an IC50 value of 0.001 mg ml, rod-shaped zinc oxide NPs made from Lilium ledebourii tuber extract suppressed the growth of L. major [29]. Saleh [30] also found that green TiO2 nanoparticles were efficient in reducing L. tropica toxicity in male rats. Hematite (Fe2O3) NPs made from Rhus punjabensis extract were found to be effective in the treatment of leishmaniasis [31]. Khalil et al. [32] used aqueous leaf extracts of Sageretia thea to make lead oxide NPs (PbO-NPs). PbO-NPs were found to be significantly active in stopping the growth of promastigote and amastigotes forms of L. tropica, with IC50 values of 14.7 and 11.95 g/ml, respectively. Plant-mediated iron oxide nanoparticles (Trigonella foenum-graecum) have been shown to have considerable inhibitory effects on L. tropica [33]. Abbasi et al. [34] also indicated that NiO-NPs made from Geranium wallichianum has antileishmanial activity against L. tropica.

In addition, the nanostructured drug delivery method has been shown to help with NTDs like leishmaniasis. Furthermore, crude plant extracts and specific phytoconstituents produced from plants that are involved in the preventative mechanism were loaded into the nanostructured drug delivery system and used as a therapeutic source to cure leishmaniasis, as shown below:

  • Liposome NPs containing phospholipids are used as a transport system for the delivery of both hydrophilic and lipophilic medicinal medicines [35]. They give superior pharmacokinetic assets as well as target diligence, which is a significant benefit [36]. Through phagocytosis, liposomes can spear macrophages and transport medications directly to their target areas. Various medication formulations, such as AmB colloidal formulations, liposomal AmB, and the AmB lipid network, can significantly reduce the toxicity of traditional pharmaceuticals [20].

  • Antileishmanial effects of liposome-encapsulated Curcuma longa and Combretum leprosum extracts have also been discovered [37, 38].

  • The usage of beta-lapachone isolated from the Lapacho tree and encapsulated with lecithin-chitosan NP has been described in the treatment of leishmaniasis [20].

  • Leishmania has been treated with 8-hydroxyquinoline encapsulated in polymeric micelles [39]. Berberin is an isoquinoline alkaloid derived from medicinal plants that has been shown to have a variety of biologic features, including antileishmanial activity. In VL, a prior study focused on the development of BER-loaded liposomes with the goal of preventing rapid liver metabolism and improving drug selective delivery to diseased organs [40].

According to the literature review, plant-based nanoparticles play an effective function in the treatment of leishmaniasis when compared to other treatments. At a far lower concentration than the required dose of Amp B to cure this condition, phytosynthesized NPs had the same effect on parasite growth suppression. Furthermore, green bimetallic nanoparticles such as Au-Ag, Zn-Ag, and Ti-Ag were produced and successfully used as a medicinal source to treat leishmaniasis [28]. Because of its nontoxic, safe, and efficient vaccine delivery technique, NPs are recommended above other medicinal options to treat this dreadful disease. With the progress of nanosciences, a new way of producing vaccines employing NPs as antigen carriers is now available. Solid lipid nanoparticles may be useful in the development of a leishmanial vaccine [41]. However, no NP-based vaccination is currently available, and further research is required.


5. Restorative mechanism of nanoformulations against leishmaniasis

The protozoan parasite Leishmania spp. causes cutaneous and visceral leishmaniasis. Depending on the immune responses induced by the diseased host, several clinical investigations show the development of self-curable to adverse situations [42]. Pentavalent antimonials (such as sodium stibogluconate or meglumine antimoniate) and other antileishmanial medications (amphotericin B, fluconazole, pentamidine, and miltefosine) are the most effective treatments for leishmaniasis. However, undesirable effects, high costs, complicated infusion routes, low cure rates, and rising resistance are all major concerns when it comes to developing more effective leishmaniasis treatments. Furthermore, the efficacy of the medicine employed in treatment differs per leishmanial species [28, 40, 42]. In self-treatment, phagocytes recognize and devour the causative agents, causing Leishmania assassination by releasing reactive oxygen species, nitric oxide, and tumor necrosis factors [43]. Following innate immune responses, TH1 immunity activates and produces CD8+, NK, and IFN cells, which kills the Leishmania parasites [42]. In sensitive situations, the defense system fails to overcome infections, resulting in erroneous TH2 immune responses as well as antibody responses, which is the main factor in developing new parasite elimination methods. Infected cells’ proliferation and viability are inhibited by metal nanoparticles, which is dependent on the NP strength and exposure period [44, 45]. Several in vitro and in vivo data imply that bio-Ag-NPs have leishmanicidal actions via direct (non-inflammatory) or indirect (immunomodulatory) mechanisms [40, 45]. Metal-NPs destroy parasitic cells directly by producing vacuolation within the parasites and disruption to the cellular membrane, without generating immunomodulatory intermediaries such as reactive oxygen species (ROS), nitric oxide (NO), and apoptotic and necrotic factors [45]. Nanoformulations aid site-specific delivery and accumulation of medicines, which is responsible for parasite killing, when Leishmania parasites override the oxidative burst inside phagocytic cells and dwell in phagolysosomes [46]. According to Fanti et al. (2018) [45], Ag-NPs are oxidized by acidic conditions within the phagolysosomes following passage through the cellular membranes, and the release of free Ag + ions induces parasite assassination. The indirect strategy, on the other hand, includes inducing immunomodulatory responses at infection sites. Other methods of providing leishmanicidal effects include activating immune response mediators and reducing cell viability and proliferation as a result of metallic nanoparticles. NPs cause a variety of morphological changes, including distorted membrane integrity, cytotoxicity, mitochondrial destruction, cell cycle arrest (G1), increased/decreased ROS and NO production, altered enzymatic activity, and the release of apoptotic or necrotic components [47, 48, 49]. As a result of mitochondrial disintegration, ATP production is harmed, which leads to cytotoxic effects and, in turn, impairs infection growth [50]. Furthermore, NP exposure results in a lower parasitic load and a decrease in the trypanothione reductase system, which is an important parasitic enzyme [45].


6. Conclusions

Chemotherapy has become the only option for treating leishmaniasis due to a lack of effective medicines. However, these medications have increased degrees of toxicity, treatment costs, and resistance development against leishmanial parasites, as well as other side effects. Furthermore, due to leishmanial antigen variations and varied immunological responses to the treatment, the efficacy of medicines differs from species to species. Biogenic nanomaterials have been suggested as helpful alternatives to formulate nanovaccines since they are nontoxic, biocompatible, cost effective, and have high targeted drug-loading potentials. Nanoformulations can be used to overcome targeted medication transport hurdles, resulting in increased parasiticidal efficacy. Moreover, plant-derived natural compounds (such as berberine, 7,8-dihydroxyflavone, E-caryophyllene, essential oil constituents, -terpineol, glycosides, tannins, and anthraquinone flavonoids) have been shown to have leishmanicidal activities in various studies, which can further integrate beneficial outcomes. Furthermore, the majority of leishmanicidal investigations revealed only the most basic results, such as determining the influence of test medications (crude extract, extracted bioactive components, essential oil, and purified fraction) on parasite growth. Few of them are able to determine the right formulation as well as the effect on the sandfly promastigote stage (vector). Plants include a range of bioactive chemicals, and the majority of them have been recognized for their medicinal qualities, according to the literature. As a result, standardization may lead to the identification of a specific component that has leishmanicidal properties. Biosynthesized nanoparticles mostly remove infection by triggering the host’s immunomodulatory response or, in rare cases, directly by causing parasitic cell vacuolization, resulting in parasite death. Nanovaccines are a relatively new concept in Leishmania treatment, and while no vaccine is currently available, research is ongoing to find effective nanovaccines. Although nanotechnology has given hope for better and more successful eradication of neglected tropical diseases, a complete understanding of the molecular mechanisms responsible is still needed.


Conflict of interest



Notes/thanks/other declarations

All authors declare that they have no known competing financial interest or personal relationship that could have appeared to influence the work reported in this chapter.


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Written By

Nargis Shaheen, Chaitenya Verma and Naveeda Akhter Qureshi

Submitted: 01 August 2021 Reviewed: 09 December 2021 Published: 13 April 2022