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Halophyte Plants as Sources of Anthelmintic Agents: History
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Contributor: Maria João Rodrigues , Catarina Pereira ,
Marta Oliveira
, Gokhan Zengin , Luísa Custódio

Parasitic diseases, especially those caused by protozoans and helminths, such as malaria, trypanosomiasis, leishmaniasis, Chagas disease, schistosomiasis, onchocerciasis, and lymphatic filariasis, are the cause of millions of morbidities and deaths every year, mainly in tropical regions. Nature has always provided valuable antiparasitic agents, and efforts targeting the identification of antiparasitic drugs from plants have mainly focused on glycophytes. Salt-tolerant plants (halophytes) have attracted the interest of the scientific community due to their medicinal assets, which include antiparasitic properties.

  • plants
  • antiparasitic agents

1. Introduction

Human parasitic diseases are predominantly linked to tropical or subtropical areas. However, climate change and the increased mobility of humans and animals trigger vector migration and the upsurge of parasitic infections in developed countries. Parasitic diseases continue to play a major role in human health, particularly infections caused by protozoans and helminths, such as malaria, trypanosomiasis, leishmaniasis, Chagas disease, schistosomiasis, onchocerciasis, lymphatic filariasis, and helminthiases, which are common in tropical regions and cause millions of morbidities and deaths every year [1][2].
For centuries, nature has been a source of medicines for the treatment of a vast array of diseases, with the first records of the ethnomedicinal uses of plants dating back to 2600 BC in Mesopotamia [3]. The easy access to terrestrial plants helps to explain their popularity as a source of bioactive products and innovative drug leads used in the pharmaceutical industry [4]. The importance of plant-based molecules as antiparasitic agents was reinforced by the Nobel Prize laureates in physiology or medicine in 2015, where Youyou Tu was honored for her discovery of artemisinin, a novel drug for the therapy against malaria, which was derived from Artemisia annua L., a plant used in the Chinese traditional medicine [5].
Most research targeting the identification of antiparasitic agents has focused on glycophytes, but salt-tolerant plants (halophytes) have lately aroused the interest of the scientific community due to their multiple medicinal properties, including antiparasitic activities. The harsh habitats where halophytes thrive, such as salt marshes, maritime dunes, and marine cliffs, expose them to extremely variable abiotic conditions, including salinity, light intensity, drought, and temperature [6][7]. This stressful environment contributes to the synthesis and accumulation of bioactive metabolites, including phenolics, alkaloids, and terpenes, conferring to halophyte species important medicinal properties, such as antioxidant, anti-inflammatory, antimicrobial, anti-tumoral, anti-infective, and antiparasitic activities [8][9][10][11][12][13][14][15]. In fact, several halophyte species are used as medicinal (e.g., Mesembryanthemum edule L. (syn. Carpobrotus edulis L.), and/or dietary plants (e.g., Chenopodium quinoa Willd, Salicornia spp.), mainly in rural areas where traditional medicine is the only source of health treatments. Moreover, as the problems associated with the salinization of soils and water bodies and the increasing competition for scarce freshwater resources increase [16][17], recruiting wild halophytes with economic potential is one of the suggested strategies to reduce the damage caused by the salinization of soil and water [18]. While most of the crop species used in traditional agriculture are salt sensitive (glycophytes), having a 10% yield decrease as the soil salinity increases over the 4–8 dS/m range, the growth of several halophytes is stimulated within a salinity range of 15–25 dS/m [18]. Halophytes are, therefore, a real strategy as alternative highly salt-tolerant crops that can cope with adverse saline conditions, to be used in the exploitation of degraded agricultural lands with the irrigation with brackish water for sustainable water management and soil conservation when establishing cost-efficient and environmental-friendly agro-ecosystems.
Reports on the traditional medicinal uses of halophytes comprise 43 families and more than 180 species in the Mediterranean, the Arabian Sea, and Syrian regions [12][19][20]. Some of these halophytes, such as Chenopodium album and Artemisia ramosissima have ethnomedicinal uses for parasitic diseases, including protozoal and helminthic infections [12][18][19], and several scientific reports confirmed their activities by in vitro and in vivo methods and identified their main bioactive constituents. 

2. In Vitro Activities and Bioactive Constituents

Most of the reports on the anthelmintic activity of halophytes were performed only in vitro, and only less than half included a chemical characterization of its major constituents. Twelve species from 9 families have been described with in vitro anthelmintic properties, and those reports are included in Table 1.
Oliveira and colleagues [21] have screened 80% acetone extracts from 8 halophyte species for their anthelmintic capacity using the Larval Ensheathment Inhibition Assay (LEIA) and Egg Hatching Inhibition Assay (EHIA) for T. colubriformis. P. lentiscus, L. monopetalum, C. mariscus, and H. italicum picardi were the most active in both GINs and life stages of the nematodes [21]. In particular, C. mariscus aerial parts collected during summer were more active against T. colubriformis (EC50 = 77.8 µg/mL) [22]. Moreover, inflorescences presented the highest anthelmintic activity against T. colubriformis [EC50 (LEIA) = 78.6 µg/mL; IC50 (EHIA) = 848.2 µg/mL]. Flavan-3-ols, proanthocyanidins, luteolin, and glycosylated flavonoids are the main active components [22]. Some authors have also tested some halophyte extracts against S. mansoni, which is a helminth species and the causal agent of schistosomiasis in humans. Methanol extracts of C. ambrosioides reduced S. mansoni cercariae infectivity [23], as well as essential oils from F. vulgare that showed moderate in vitro activity against S. mansoni worms, but with more remarkable effects in egg development, possibly attributable to the two main constituents detected in the essential oil, I-anethole and limonene [24]. A compound isolated from G. inflata, licochalcone A (Figure 1), presented an LC50 of 9 μM towards S. mansoni female and male adult worms [25].
Marinedrugs 21 00066 g002 550
Figure 1. Chemical structures of pure compounds reported with anthelmintic properties.
Besides, other authors have focused on other less frequently tested parasite species. For instance, the roots of G. glabra contain glycyrrhizic acid (Figure 2) that is very active in vitro against B. malayi microfilarae (IC50 = 1.20 μM), one of the most important causative agents of human lymphatic filariasis [26].
Table 1. In vitro anthelmintic activity of halophyte species.
Family/Species Plant Organ Extract/Fraction/Compound Chemical Components Assay Results References
Apiaceae            
Foeniculum vulgare Mill. Fresh leaves Essential oil I-anethole and limonene Schistosoma mansoni adult worms (pairs) and eggs 50% activity at 100,000 µg/mL (24 and 120 h) [24]
Asteraceae            
Helichrysum italicum (Roth) G. Don subsp. picardi (Boiss. & Reut.)
Franco		 Aerial parts 80% acetone extract Caffeoylquinic and dicaffeoylquinic acids and quercetin glycosides Trichostrongylus colubriformis IC50 (LEIA) = 132 µg/mL; IC50 (EHIA) = 3707 µg/mL [21]
Inula crithmoides L. Aerial parts 80% acetone extract ND Trichostrongylus colubriformis IC50 (LEIA) = 1031 µg/mL [21]
Cyperaceae            
Cladium mariscus L. Pohl Aerial parts 80% acetone extract Proanthocyanins, phenolic
acids, and luteolin		 Trichostrongylus colubriformis IC50 (LEIA) = 77.8 µg/mL; IC50 (EHIA) = 2575 µg/mL [21]
  Aerial parts, leaves, and inflorescences collected during spring, summer, autumn, and winter 80% acetone extract Flavan-3-ols,
proanthocyanidins, luteolin, and glycosylated flavonoids		 Trichostrongylus colubriformis Summer: EC50 (LEIA) = 77.8 µg/mL; Spring: IC50 (EHIA) = 2275 µg/mL; Leaves: EC50 (LEIA) = 81.1 µg/mL; IC50 (EHIA) = 2289 µg/mL;
Inflorescences: EC50 (LEIA) = 78.6 µg/mL; IC50 (EHIA) = 848 µg/mL		 [22]
Convolvulaceae            
Calystegia soldanela (L.) R. Br. Aerial parts 80% acetone extract ND Trichostrongylus colubriformis IC50 (LEIA) = 2711 µg/mL [21]
Fabaceae            
Glycyrrhiza glabra L. Roots Glycyrrhizic acid   Brugia malayi microfilarae in vitro IC50 = 1.20 μM [26]
Glycyrrhiza inflata Batalin ND Licochalcone A   S. mansoni (female and male adult worms) LC50 = 9 μM [25]
Medicago marina L. Aerial parts 80% acetone extract ND Trichostrongylus colubriformis IC50 (LEIA) = 211 µg/mL [21]
Plantaginaceae            
Plantago coronopus L. Aerial parts 80% acetone extract ND Trichostrongylus colubriformis IC50 (LEIA) = 212 µg/mL [21]
Plumbaginaceae            
Limoniuastrum monopetalum (L.) Boiss. Aerial parts 80% acetone extract Sulphated and/or methylated flavonoids Trichostrongylus colubriformis IC50 (LEIA) = 1024 µg/mL; IC50 (EHIA) = 2102 µg/mL [21]
Poaceae            
Cynodon dactylon (L.) Pers. ND Methanol extract ND Hymenolepis
diminuta		 40,000 µg/mL: paralysis and mortality at 4.12 h and 5.16 h, respectively [27]
Rubiaceae            
Crucianella marítima L. Aerial parts 80% acetone extract ND Trichostrongylus colubriformis IC50 (LEIA) = 1024 µg/mL [27]
ND: not determined.

3. In Vivo Studies

There is a reduced number of studies focusing on in vivo anthelmintic properties of halophytic species. In fact, to our best knowledge, only three species were tested, mostly using rodents and sheep as models (Table 2).
Pistacia lentiscus is the most studied halophyte species due to its high level of tannins, known to exhibit high anthelmintic activity, as confirmed by in vivo studies against T. colubriformis. Infected goats fed with aerials parts of P. lentiscus presented a 16% reduction in fecal oocyst counts, whereas, in lambs, the reduction ranged between 55.2 and 61.3% [28][29]. In turn, S. mansoni infected mice treated orally with a methanol extract of C. ambrosioides (1250 mg/kg/day) exhibited a 53.7% total worm burden decrease and a 60.3% ova/g tissue in liver reduction, 9 weeks post-infection [30]. Hymenolepis diminuta infected Wistar rats were treated with C. dactylon methanol extract (800 mg/kg) enabling a reduction of 77.6% in eggs and 79% in adult worms counts, respectively [27].
Table 2. In vivo anthelmintic activity of halophyte species.
Family/Species Plant Organ Extract/Fraction/Compound Chemical Components Assay Results References
Amaranthaceae            
Dysphania ambrosioides (L.) Mosyakin & Clemants (syn. Chenopodium ambrosioides L.) ND Methanol ND S. mansoni infected mice 1250 mg/kg/day exhibited a 53.7% total worm burden decrease and a 60.3% ova/g tissue in liver reduction [23][30]
Anacardiaceae            
Pistacia lentiscus L. Aerial parts ND Tannins Teladorsagia circumcincta, Trichostrongylus colubriformis, and Chabertia ovina infected goats Reduced fecal oocyst counts in approx. 16% [29]
    ND Tannins T. colubriformis infected lambs Reduction of 55.2–61.3% on faecal egg counts [28]
Poaceae            
Cynodon dactylon (L.) Pers. ND Methanol extract ND Hymenolepis
diminuta infected Wistar rats		 800 mg/kg: 77.6 and 79% reduction in egg and worms’ reduction, respectively [27]
ND: Not determined.

This entry is adapted from the peer-reviewed paper 10.3390/md21020066

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