Subcutaneous filariasis or onchocerciasis is a parasitic disease that is caused by O. volvulus. The cattle parasite O. ochengi is the closest known relative of O. volvulus with which it shares the same arthropod vector, Simulium damnosum. The O. ochengi system fills the critical niche between laboratory studies in rodent models and field evaluation of onchocerciasis control in human populations. The cattle—O. ochengi model equals that of human onchocerciasis, with nodules that closely resemble those formed by O. volvulus[25]. Thus it is feasible that medicinal plants, traditionally used by farmers against the bovine parasite, also affect the human parasite O. volvulus.

Nyasse et al. [26] demontrated that polycarpol from Polyalthia suaveolens (Annonaceae) and 3-O-acetyl aleuritolic acid from Discoglypremna caloneura (Euphorbiaceae) exhibited significant inhibitory activities on the vitality of adult male worms of Onchocerca gutturosa.

Further studies were conducted by Cho-Ngwa et al. [27] on O. ochengi. These authors reported microfilaricidal activity of the hexane extract of Homalium africanum (Salicaceae) leaves, the hexane extract of Margaritaria discoidea (Euphorbiaciaea) roots, the methylene chloride extract of H. africanum leaves and the methylene chloride extract of M. discoidea leaves. However, none of the plants used showed macrofilaricidal activity. These Salicaceae and Euphorbiaceae are commonly used in the traditional treatment of onchocerciasis in North West Cameroon.

Using the cattle parasite O. ochengi, Ndjonka et al. [28] reported that ethanolic extracts of the bark of Anogeissus leiocarpus (Combretaceae) and Khaya senegalensis (Meliaceae) as well as leaves of K. senegalensis and Euphorbia hirta (Euphorbiaciaea) display high macro- and microfilaricidal activities, while aqueous extracts of leaves from Parquetina nigrescens (Asclepiadaceae) and Annona senegalensis (Annonaceae) displayed a more moderate effect on the worms viability. This was also observed using Caenorhabditis elegans, a highly suitable and free-living model organism for research on nematode parasites. Furthermore, some selected plants showed toxicity not only against wildtype C. elegans but also against drug resistant (ivermectin, levamisole and albendazole) strains [29]. Here, the most promising plant was A. leiocarpus (Combretaceae) with a high toxicity against O. ochengi, C. elegans wildtype and C. elegans drug resistant strains [29]. The phytochemical analysis of an A. leiocarpus extract showed a high amount of tannins, which have been reported to have a certain anthelmintic activity [30,31]. Tannins present in their composition several phenolic groups such as ellagic, gallic and gentisic acids. Gallic and gentisic acids have been reported to be toxic for C. elegans[30]. Recently, we showed that ellagic acid exhibited higher toxicity against C. elegans wildtype and drug resistant strains (Ndjonka and Liebau, personal communication). High microfilaricidal and macrofilaricidal activities were also reported with ellagic acid [29].

Thomsen et al. [32] used the anthelmintic active extracts of Hagenia abyssinica (Rosaceae) to develop a simple and inexpensive bioassay against the non-parasitic nematode C. elegans.

Katiki et al. [33] demonstrated that extracts rich in hydrolysable tannins such as Acer rubrum (Aceraceae), Rosa multiflora (Rosaceae) and Quercus alba (Fagaceae), or extracts rich in both hydrolysable and condensed tannins such as Rhus typhina (Anacardiaceae), were significantly more lethal to adult of C. elegans than extracts containing only condensed tannins such as Lespedeza cuneata (Fabaceae), Salix X sepulcralis (Salicaceae) and Robinia pseudoacacia (Fabaceae).

Our online search on medicinal plants used against onchocerciasis found nine publications since 2002, where a total of 17 plant species, belonging to 10 different families, have been studied. In these studies, only five pure compounds were isolated (Table 1).

LF is a parasitic disease that is caused by Brugia sp. and W. bancrofti. Current control programs outside sub-Saharan Africa use DEC plus albendazole or DEC alone, while in Africa ivermectin plus albendazole is used because of contraindications for DEC in patients infected with O. volvulus[16,17]. However, there is no effective drug that targets the adult stage of the worms. Based on the observation that filarial worms depend on the endosymbiontic bacteria Wolbachia for metabolic and reproductive activities, doxycycline therapy is suggested by Hoerauf et al. [49] and Taylor et al. [50] for individual drug administration in bancroftian filariasis.

Several plants have been assessed for their antifilarial activity against Brugia sp and W. bancrofti. Lakshmi et al. [34] conducted a study on the antifilarial activity of a marine red alga, Botryocladia leptopoda (Rhodymeniaceae) against experimental infections with the rodent filarial parasites Litomosoides sigmodontis and Acanthocheilonema viteae and the human-pathogenic B. malayi. They show that the ethanolic crude extract and its hexane fraction reduce microfilarial levels and kill a significant proportion of the adult worms from L. sigmodontis and A. viteae. In the case of B. malayi, the macrofilaricidal efficacy was much less than that observed in the rodent parasites, but significant sterilization of the surviving female parasites was caused by the hexane and chloroform fractions of the ethanolic crude extract of B. leptopoda.

Fujimaki et al. [35] screened and provided detailed informations about 11 medicinal plants used in Guatemala for in vitro macrofilaricidal activity against B. pahangi. Among the 11 medicinal plants, the ethanolic extract of leaves of Neurolaena lobata (Asteraceae) showed the highest inhibitory activity against the motility of adult worms. The in vitro assay of the extract of N. lobata showed potential macro- and micro-filaricidal activities.

Misra et al. [36] reported the antifilarial activity in the extract of stem portions of the plant Lantana camara (Verbenaceae). They showed that the ethanolic crude extract of this plant administered orally to the rodent model Mastomys coucha killed 43.05% of adult B. malayi and sterilized 76% of surviving female worms. After fractionation of the ethanolic extract of this Verbenaceae, Misra et al. [36] were able to show that the chloroform fraction contains 34.5% adulticidal activity along with sterilization of 66% of female worms. They also demonstrated that the activity of L. camara depends on the rodent host. Thus, using Meriones unguiculatus (gerbil) rodents as host for B. malayi, lead to an antifilarial activity up to 80%, whereas at the same dosage, all adult worms were killed using M. coucha as host. The authors also reported that L. camara is efficient against the A. viteae, exerting strong microfilaricidal (95.04%) and sterilization (60.66%) efficacy with mild macrofilaricidal action. Two compounds from L. camara, oleanonic acid and oleanolic acid, isolated from hexane and chloroform fractions also showed an in vitro activity against B. malayi adults. Toxicity studies of L. camara in rats showed that all rats remained active and healthy throughout the study [34].

Sahare et al. [37,51] analyzed the in vitro effect of Butea monosperma (Fabaceae), Vitex negundo (Lamiaceae), Aegle marmelo (Rutaceae) and Ricinus communis (Euphorbiaceae) on the motility of B. malayi microfilariae. They reported that aqueous extract of B. monosperma leaves, ethanolic extract of V. negundo root and ethanolic extract A. marmelo leaves exhibited a 100% inhibition of motility of microfilariae at 100 ng/mL concentration as compared to controls. At the same concentration, methanolic extract of R. communis leaves and aqueous extract of B. monosperma roots showed no significant activity on the motility of B. malayi microfilaria. Using thin layer chromatography, Sahare et al. [51] were able to reveal the presence of alkaloids, saponin and flavonoids in the roots of V. negundo and coumarin in the leaves of A. marmelos.

Gaur et al. [39] studied the antifilarial activity of Caesalpinia bonducella (Caesalpiniaceae) seed kernel by using cotton rats Sigmodon hispidus and M. coucha that harbor the filarial parasites L. sigmodontis and B. malayi, respectively. Oral treatment of the rats with ethanolic extract of C. bonducella significantly reduced the number of microfilariae and macrofilariae of L. sigmodontis, with up to 96% filaricidal activities and 100% female sterilizing efficacy. Furthermore, Gaur et al. [39] reported that the butanol and the aqueous fraction exerted 73.7% and 90% reduction of microfilariae number, respectively, and 82.5% mortality in adult worms with 100% female sterilization for both fractions, while two hexane fractions lead to 64% and 95% macrofilaricidal activity and 100% worm sterilization. However, in the B. malayi/M. coucha model, the hexane fraction that demonstrated high macrofilaricidal activity on L. sigmodontis, only showed a gradual microfilaraemia reduction and caused 80% sterilization of female parasites. These results suggest that C. bonducella seed kernel extract and fractions show microfilaricidal, macrofilaricidal and female-sterilizing efficacy against L. sigmodontis and microfilaricidal and female-sterilizing efficacy against B. malayi. This indicates the potential of the plant in providing a lead for new antifilarial drug development [39].

Mathew et al. [40] investigated the in vitro activity of a methanolic extract of fruits of Trachyspermum ammi (Apiaceae) against adult bovine filarial Setaria digitata worms. Using high-performance liquid chromatography, they isolated the active fraction containing a phenolic monoterpene. After characterization, the active molecule showed macrofilaricidal activity and sterilizing efficacy against B. malayi in M. coucha. After extraction of leaves of Piper betle (Piperaceae) in methanol, Singh et al. [41] studied the antifilarial activities of the crude extract, the n-hexane and chloroform fractions of this Piperaceae using B. malayi. They demonstrated that the methanolic crude extract, the hexane and chloroform fractions of P. betle in vivo contain remarkable immunomodulatory properties in BALB/c mice and enhance both humoral as well as cell-mediated immune responses. Furthermore, in vivo antifilarial activity of the crude methanol extract and its active fractions was assessed using B. malayi, experimentally maintained in M. coucha, and the antifilarial results correlated with the immunomodulation potential of the plant. The crude extract and its active fractions suppressed microfilaraemia, showed moderate adulticidal activity and female worm sterilization.

Sharma et al. [38] selected extracts of roots of Vitex negundo, leaves of Butea monosperma, Aegle marmelos and Ricinus communis, to explore the possible involvement of any oxidative mechanisms in the observed antifilarial effect. They observe the presence of polyphenolic compounds and an increase in oxidative parameters in V. negundo, B. monosperma and A. marmelos and conclude that the observed antifilarial action of these herbal extracts might be associated with oxidative stress.

Misra et al. [42] studied the antifilarial activity of fruits of Xylocarpus granatum (Meliaceae) against B. malayi in vivo using the jird model M. unguiculatus and M. coucha. The in vitro effect of crude aqueous extract from different parts of X. granatum on filarial parasites was reported earlier by Zaridah et al. [43]. In their studies, Misra et al. [42] demonstrated that the crude aqueous ethanolic extract was active in vitro and demonstrated a 52.8% and 62.7% adulticidal and embryostatic effect on B. malayi in vivo, transplanted in the jird model (M. unguiculatus) and M. caucha. After fractionation (ethyl acetate fraction, n-butanol fraction, water-soluble fraction and water-insoluble fraction), only the ethyl acetate fraction revealed in vivo activity. Eight pure molecules were isolated from the active fraction, with the two compounds gedunin (IC₅₀ = 0.239 μg/mL, SI = 889.1) and photogedunin (IC₅₀ = 0.213 μg/mL, SI = 1231.4) at 5 × 100 mg/kg by subcutaneous route revealed adulticidal efficacy, with 80% and 70% mortality of the transplanted B. malayi.

Sashidhara et al. [44] isolated galactolipid from Bauhinia racemosa (Caesalpinaeceae). They showed that the leaves of B. racemosa exhibit promising in vitro and in vivo antifilarial activity against B. malayi which can be attributed to the presence of one pure compound, namely (2S)-1,2-di-O-linolenoyl-3-O-a-galactopyranosyl-(1/6)-O-b-galactopy ranosyl glycerol.

Azeez et al. [45] identified 10 spices and medicinal plants, namely coriander (Coriandrum sativum, Apiaceae), cassia (Cassia, Fabaceae), turmeric (Curcuma longa, Zingiberaceae), allspice (Pimenta dioica, Myrtaceae), cinnamon (Cinnamomum, Lauraceae), strychnous (Strychnos, Loganiaceae), lemongrass (Cymbopogon, Poaceae), garlic (Allium sativum, Amaryllidaceae), litsea (Litsea, Lauraceae) and vanilla (Vanilla, Orchidaceae) that contain phytochemicals, with the potential to inhibit the detoxification enzyme glutathione S-transferase (GST) from B. malayi. Molecular docking of these compounds, followed by in vitro GST assay, demonstrated that linalool, alpha-pinene, strychnine, vanillin, piperine, isoeugenol, curcumin, beta-caryophyllene, cinnamic acid, capsaicin, citronellol and geraniol effectively inhibit the B. malayi GST and therefore mark them as lead compounds.

Kushwaha et al. [46] reported that chemotypical variations in Withania somnifera (Solanaceae) lead to differentially modulated immune responses in BALB/c mice. Furthermore, the published findings [48] on the different immunomodulatory and immunotherapeutic potentials for the crude oil of Nigella sativa (Ranunculaceae) seeds and its active ingredients led Kushwaha et al. [47] to hypothesize that immunostimulation prior to pathogen invasion might provide protection against filarial infection. They demonstrated that crude root extracts of chemotypes NMITLI-101 (101R), NMITLI-118 (118R) and NMITLI-128 (128R) as well as withanolide withaferin A of W. somnifera offer protection to the rodent host M. coucha against infection of filarial parasite B. malayi. They also showed that treatment with W. somnifera extracts negatively affected not only larval establishment in the host but also led to a defective embryogenesis in female worms. This study revealed the potent immunoprophylactic property of W. somnifera.

Our online search on medicinal plants used against LF found 16 publications since 2002, where a total of 24 plant species, belonging to 20 different families, have been studied on. In these studies 24 pure compounds were isolated (Table 1).

In former times, chemotherapy against Schistosoma sp. infection depended on antimonials. Due to serious side effect caused by these drugs, the use as schistosomicidal drugs was discontinued and currently the treatment mainly relies on three compounds: metrifonate, oxamniquine and praziquantel [64,65].

Vegetable oil extracts probably constitute the first anthelmintic products in traditional medicine. The variety of their application modes evidenced the ethno-pharmacological potential of these extracts as sources of active compounds. However, there are only a few studies which are focusing on the isolation, the identification, and eventually the validation of the active molecules within the plant extracts [93–98]. More recently, an initiative of research groups all over the world has been founded to set up plant extract screening programs [99–103]. A variety of compounds that reveal schistosomicidal activity have been identified in in vitro assays (Table 2). However, the extrapolation of in vitro results to the “in vivo world” is far away from being trivial. A good example for this is Vernodalin (Table 2), a sesquiterpene lactone with a promising in vitro activity but no in vivo activity [104]. Even after promising results are obtained in in vivo studies, the application of this drug in an endemic region must take other factors into consideration, such as the presence of other infectious pathogens. These could cause co-infections and thereby interfere with the respective treatment. For example, the antimalarial activity of Artemisinin and some derivatives has been exploited for more than 20 years [105]. More recently, the discovery and in vivo validation of schistosomicidal activity of artemisinin was established by observing a reduction of the parasitaemia in experimentally S. japonicum infected mice and the susceptibility of schistosomula to the drug [106–108]. Later, these results were also confirmed for S. mansoni. Within this study, an increased sensitivity of the females to the drug was also observed [109]. Although these results were promising, the use of artemisinin in regions endemic for malaria should be carefully assessed, since the application of this drug to control schistosomiasis could have the serious adverse side effect of increasing artemisinin drug resistance in malaria [110,111].

Synthetic drugs and natural compounds with schistosomicidal activity in general lead to alterations in their behavior (disruption of mating of males and females, reduction in reproductive fitness), in the morphology or constitution of the protective tegument, or in the muscle activity of the parasite.