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The leishmanicidal activity of essential oils: A systematic review

Introduction Leishmaniasis is one of the most important vectortransmitted diseases which has the second rank after malaria in terms of mortality caused by a parasite disease (1). Leishmaniasis is currently endemic in 102 countries. Countries such as Iran, Afghanistan, Syria, Algeria, North Sudan, Ethiopia, Peru, Colombia, Costa Rica, and Brazil have the highest incidence of leishmaniasis (2,3). An estimated 700 000 to 1 million new cases, and 26 000 to 65 000 deaths occur, annually (4). Leishmaniasis is caused by an obligate intracellular parasite of the genus Leishmania (Trypanosomatida) (5) and transmitted by the bite of infected females of sand flies (Family: Phlebotominae) (6). This disease can be seen in various forms, including cutaneous, visceral, and mucosal leishmaniasis (7). Leishmania parasites have two forms in their life cycle, including amastigote and promastigote (8). Considering the growing number of new cases, the development of new drugs is critical. Plant-derived essential oils (EOs) are natural oil that secreted as secondary metabolites from different parts of the aromatic plants (9). EOs composed of a mixture of hydrophilic and hydrophobic molecules (10). They possess various biological activities such as larvicidal effect (11), antibacterial properties (12), and antifungal aspect (13), and introduces an excellent source for finding new drugs (14). Recently leishmanicidal activities (LCA) of EOs have received much attention. Moreover, their effects on promastigotes of different species of Leishmania have been http://www.herbmedpharmacol.com doi: 10.34172/jhp.2020.38


Introduction
Leishmaniasis is one of the most important vectortransmitted diseases which has the second rank after malaria in terms of mortality caused by a parasite disease (1). Leishmaniasis is currently endemic in 102 countries. Countries such as Iran, Afghanistan, Syria, Algeria, North Sudan, Ethiopia, Peru, Colombia, Costa Rica, and Brazil have the highest incidence of leishmaniasis (2,3). An estimated 700 000 to 1 million new cases, and 26 000 to 65 000 deaths occur, annually (4).
Leishmaniasis is caused by an obligate intracellular parasite of the genus Leishmania (Trypanosomatida) (5) and transmitted by the bite of infected females of sand flies (Family: Phlebotominae) (6). This disease can be seen in various forms, including cutaneous, visceral, and mucosal leishmaniasis (7). Leishmania parasites have two forms in their life cycle, including amastigote and promastigote (8).
Considering the growing number of new cases, the development of new drugs is critical. Plant-derived essential oils (EOs) are natural oil that secreted as secondary metabolites from different parts of the aromatic plants (9). EOs composed of a mixture of hydrophilic and hydrophobic molecules (10). They possess various biological activities such as larvicidal effect (11), antibacterial properties (12), and antifungal aspect (13), and introduces an excellent source for finding new drugs (14).
Recently leishmanicidal activities (LCA) of EOs have received much attention. Moreover, their effects on promastigotes of different species of Leishmania have been reported frequently (15,16). In this research, the LCA of EOs on different types of promastigotes systematically have been reviewed, form January 1, 2000 to June 30, 2019.

Data collection
Due to much publication on investigating LCA of EOs, data collection was included just to PubMed website (https://www.ncbi.nlm.nih.gov/pubmed/advanced). Steps for finding proper reports were described as follow: Full texts of all 120 papers were collected. Required information including scientific names of plants, parts of used for EOs extraction, and inhibitory concentration 50% (IC50) were also extracted. Fifty-five articles that had no reported IC50 were excluded. It should be noted that IC50 is a quantitative measure that indicates how much of an EO is needed to inhibit 50% of promastigotes growth in comparison to control groups, no treated with EO.
The most common form of leishmaniasis is cutaneous leishmaniasis, which causes several types of skin lesions on exposed parts of the body such as ulcers, leaving lifelong scars and severe disability or stigma (55,56). Table 3 reports the LCA of many EOs against L. chagasi.  In the new world, visceral leishmaniasis is associated with L. Chagasi (60). As details show, IC50 of 3 EOs, including Copaifera reticulate, Lippia citriodora, and Lippia origanoides, are around 5 µg.mL -1 . These EOs are suitable candidates for in-vivo studies. A fatal form of leishmaniasis is visceral, in which parasite affects internal organs such as the spleen, liver, and bone marrow (61). Table 4 shows the leishmanicidal potency of eight EOs on L. donovani. In India and West Africa, L. donovani is the causative agent of visceral leishmaniasis (Kala-azar) (67). Among the reported IC50s, EOs of Artemisia annua, Piper auritum, and Syzygium aromaticum with values of 14.60, 12.80, and 21.00 µg.mL -1 respectively, were more effective than others (54,68,69).
Results of LCA of some medicinal plants on L. major are summarized in Table 6. L. major and L. tropica in the old world are responsible for cutaneous leishmaniasis (7). Interestingly 3 documented IC50s were around 1 µg.mL -1 ; those values were related to EOs of Mentha pulegium, Rosmarinus officinalis, and Thymus hirtus. Table 7 summarizes the effect of many EOs on L. mexicana, which is one of the primary causes of cutaneous     were more effective than others (86). Table 8 briefs the effect of 9 plant-derived EOs on L. panamensis promastigotes. Recently, it revealed that L. panamensis found in Central and South America, as well as it is the causative agent of the mucosal form (89). Origanum vulgare EO with IC50 of 42.23 µg.mL -1 was better than others (58).
Results of LCA of many EOs on promastigotes of L. tropica are given in Table 9. In the Middle East and North Africa, L. tropica and L. major are two main causative agents of human cutaneous leishmaniasis (7). Results demonstrated that 2 EOs, including Myrtus communis   Zataria multiflora Boiss Aerial parts 89.30 (91) and Nigella sativa with IC50 of 8.40 and 9.30 µg.mL -1 respectively, were potent than others.

Conclusion
The articles published over the last 20 years on the leishmanicidal activity of EOs have been systematically reviewed. IC50s of 179 EOs on promastigotes of 9 different species of Leishmania were also documented, separately. Interestingly, thirty-five of IC50 values were lower than 10 µg.mL -1 , thus could be introduced for further investigations such as preparation of nano/formulations, performing in-vivo studies, and clinical trials. However, given the selective properties of EOs, their combination can lead to good results. In other words, depending on the endemic leishmaniasis, EOs can be combined and formulated as multifunctional drugs. In addition, the categorized results in this research would be an excellent guide for other researchers to select proper EOs.
Authors' contributions SNG contributed to the extraction of information from literature and providing of information on leishmaniasis. NS contributed in extraction of information from literature and providing of information on information about EOs. The idea of doing this research as well as writing the manuscript done by MO. All authors read and approved the final report.

Conflict of interests
There is no conflict of interest to declare.

Ethical considerations
Ethical issues have been observed by the authors.