Introduction

Schistosomiasis, a vector-borne water-based disease caused by Schistosoma blood flukes, is one of the most devastating parasitic diseases in tropical and subtropical regions (Walz et al. 2015). It is regarded by World Health Organization (WHO) as the third most common tropical disease, following malaria and intestinal helminthiasis (Murungi et al. 2021). It is also recognized as one of the neglected tropical diseases with high morbidity and mortality rates, affecting a billion of the world’s poorest people, mainly in the developing countries (Pereira et al. 2011). The disease is an underappreciated global burden and linked geographically to poverty, and poor health services (Payne and Fitchett 2010). It mostly affects young adults in their productive years, and children younger than 10 years. Untreated infections in young people impair their immunity, increasing their vulnerability to growth retardation, malnutrition and cognitive disorders (Dabo et al. 2011). More than 500,000 people die every year from this parasitic disease (Botelho et al. 2009).

Schistosoma has a complex lifecycle, alternately infecting mammalian hosts and snails especially S. japonicum which spreads via all kinds of mammals (Nelwan 2019). One in 30 of the total human population surveyed in endemic areas were apparently infected by Schistosoma flukes via contaminated water or direct contact with mammals hosting the parasite (Sheir et al. 2001). Molluscicides have a long history of both failures and successes in the control of schistosomiasis (Fenwick et al. 2006). Their application is now considered a key element that has significantly contributed to the decline in schistosomiasis infection and morbidity rates in a number of African countries during the last decades (Brackenbury and Appleton 1997). Chemotherapy and chemoprophylaxis with, praziquantel (PZQ), currently play a crucial role in curing, controlling and preventing the disease (Yousif et al. 2007). PZQ is highly valuable, due to its broad activity spectrum, for instance, it has a potent effect against S. mansoni especially at 6–7 weeks old infections. PZQ is thought to target the β subunits of voltage-gated Ca2+ channels in Schistosoma (Doenhoff et al. 2008). Despite the success, resistance to PZQ is apparently emerging and exacerbating challenges in the management of schistosomiasis globally (Melman et al. 2009). Pinto-Almeida and his colleagues analyze the proteome of S. mansoni PZQ-resistant adult worms and compare it with its parental fully PZQ-susceptible strain, using a high throughput LC–MS/MS identification. The results revealed that different proteins of the S. mansoni proteome in worms, were downregulated after the exposure to PZQ (Pinto-Almeida et al. 2018). Cotton and Doyle recently identified a gene responsible for PZQ resistance in experimentally selected resistant S. mansoni. This study shows that variation at or near Sm. (S. mansoni) TRPMPZQ is associated with the resistance (Cotton and Doyle 2022).

Nature has always been a valuable source of drugs and continues to deliver important drug leads (Tulp and Bohlin 2004). WHO estimates that 65–80% of the developing world’s population relies on traditional medicine to meet primary health care needs (Kumar et al. 2021) and traditional medicinal plants have supplied numerous pharmacologically active compounds (Yousif et al. 2007). Thus, considerable efforts have been made to identify plants products that are environmentally safe, non-toxic and selectively active for the integrated control of schistosomiasis, and several of them have shown promising results. For example, we have recently shown that the Egyptian medicinal plant Asparagus stipularis Forssk. has anti-schistosomal activity (El-Seedi et al. 2012). Recent reports documented the potential of some natural products such as Pulsatilla chinensis (Bunge) Regel extracts (Table 1) and its molluscicidal activity against O. hupensis. They are less harmful to non-target aquatic organisms than the reference molluscicide niclosamide (Chen et al. 2012). In addition, Agave attenuata Salm-Dyck is toxic to the target snail Bulinus africanus but has fewer (or no) adverse effects on fish and mammals (Brackenbury and Appleton 1997).

Table 1 Bioactive plant extracts reported to have mollusicidal activity against intermediate vector snails
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Both synthetic molluscicides and molluscicides derived from plants have made progress in the field of host snails eradication. The rising expense and toxicity to non-target organisms of synthetic molluscicides has rekindled interest in plant-based molluscicides (Clark et al. 1997; Zheng et al. 2021).

This review highlights the use of medicinal plants as new alternatives that could either complement or replace conventional control approaches. Potential molluscicidal plant species and their bioactive constituent based on traditional uses (Tables 2 and 3), are listed, in accordance to the literature survey done on the biological control of Schistosoma in the field using natural products, at all life stages.

Table 2 Screening of isolated mollusicicidal bioactive compounds
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Table 3 Plants species (and their localitis) used to cure schistosomiasis in patients based on traditional uses
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Life cycle of Schistosoma species

There are three main species of human helminth parasites of the genus Schistosoma: S. haematobium, found in Africa and Asia; S. mansoni, present in Africa, the Middle-East and South America; and S. japonicum, endemic in China and Southwest Asia (Colley et al. 2014). There are also two minor species, S. intercalatum and S. mekongi, found in West and central Africa (Colley et al. 2014). The adult worms are live in mesenteric vessels (S. mansoni and S. japonicum) or the vessels surrounding the bladder (S. haematobium). The females produce large numbers of eggs that migrate through the blood vessel wall or are excreted with urine or feces (Nation et al. 2020).

The lifecycles of all Schistosoma species are quite similar, requiring freshwater snails as intermediate hosts, and mammalian hosts infected via water-borne contact with the free-swimming larvae released from the snails, as illustrated in Fig. 1. (Selbach et al. 2016). The lifecycle involves sexual maturation of adult schistosomes in man and an asexual multiplicative stage in the molluscan host (Nanes Sarfati et al. 2021). Differences between the species lie mainly in the type of intermediate host snails and the infective sites in the mammalian host, although there are also differences (inter alia) in egg morphology, and rates of both egg production and infection of mammalian hosts (Salvador-Recatalà and Greenberg 2012).

Fig. 1
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Life cycle of Schistosoma

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Once eggs reach fresh water they hatch and release swimming miracidia (larvae) that infect specific aquatic snails. The genera Biomphalaria, Oncomelania and Bullinus host S. mansoni, S. japonicum, and S. haematobium, respectively (Fig. 1) (Ross et al. 2002). In the snails, the miracidia asexually multiply after a few weeks and form thousands of cercariae that leave the snail and penetrate the skin of humans (e.g. children, fishermen, farmers, and women doing daily domestic tasks in infected water) or other mammals. If the cercariae penetrate the human body, they develop into schistosomules, then mate and migrate to the perivascular or mesenteric veins (S. mansoni and S. japonicum) or urinary bladder plexus (S. haematobium), where they produce eggs and the cycle starts again (Fig. 1) (Gryseels et al. 2006). Schistosoma often live 5–10 years, and even lifespans up to 40 years have been reported (Hokke and Deelder 2001).

History of schistosomiasis

Schistosomiasis has a history in Egypt of more than 5000 years (Barakat 2013; Abou-El-Naga 2018), with reports of S. haematobium eggs in ancient mummies (Barakat 2013). The disease was described by the ancient Egyptians on medical papyri as “â-a-â” (Abou-El-Naga 2018) and Avicenna (Ibn-Sina) in his famous book “The Canon of Medicine” (Othman and Soliman 2015), Key scientific discoveries regarding the disease have also been made in Egypt. Theodor Bilharz, a German surgeon who became Chief of the Surgical Services in Kasr El-Ain Hospital and Medical School, Cairo, discovered Schistosoma worms in 1851. Their lifecycle was subsequently described by Robert Leiper, while working in Cairo, in 1915 (Di Bella et al. 2018). The Delta Nile was become a favorite habitat for breeding the host snails of both urinary and intestinal schistosomiasis (Malek 1975).

S. japonicum eggs were discovered in two Chinese ancient bodies dating back roughly to 2180 years ago. Symptoms similar to schistosomiasis were described in the earliest Chinese ancient literature of around 4700 years ago. In the mid-1950s, the first nationwide assessment of the disease indicated that schistosomiasis was endemic in 433 cities across 12 provinces globally, affecting about 11.6 million people (Zhou et al. 2021).

Distribution of schistosomiasis

Schistosomiasis is endemic in 77 countries, and most prevalent in tropical and subtropical regions (Tefera et al. 2020). It is estimated that the severe cases are located in Sub-Saharan Africa; other highly endemic areas are Yemen and the Philippine Island of Mindanao. It is also still endemic, but at lower levels, in North Africa and several Middle East countries. In Asia, it is endemic in parts of the Yangtze River Basin in China, and middle reaches of the Mekong River in Laos and Cambodia (Bergquist and Tanner 2010). In China, a national survey in 2007 revealed that the infection rate among residents in the Fork Beach endemic area was 1.87% (Chen et al. 2012). At least 3 million people in Brazil are thought to be infected by Schistosoma, and around 25 million are at risk (Chitsulo et al. 2000). It is also endemic in several Venezuelan states, and several foci in Suriname (Zoni et al. 2016).

Economic implications

Calculating economic effects of schistosomiasis is far from straightforward, but it has been estimated to cause annual losses due to disability (complete or partial) amounting to US$ 445, 16, 118, and 60 million in Africa, South-West Asia, South-East Asia and the USA, respectively (at least US$ 641 million in total). These sums do not include all costs of related public health programs, medical care or compensation for illness, which may also be substantial (Wright 1972). For instance, estimated costs for controlling schistosomiasis morbidity among school-age children by selective and mass chemotherapy are US$ 0.67 and 0.59 per infected child, respectively (Talaat and Evans 2000). Thus, reviving large-scale school-based health programs to reduce morbidity rates of school-aged children, and to improve their physical growth and cognitive development, would be very costly (Husein et al. 1996).

Globally, the number of people treated for schistosomiasis rose from 12.4 million in 2006 to 33.5 million in 2010 (Carod Artal 2012). US$150 million have been spent on controlling neglected tropical diseases, including schistosomiasis, in sub-Saharan Africa (Gray et al. 2010). In 2008, a presidential initiative was announced calling for a commitment of US$ 350 million funding by the USA over five years to combat neglected tropical diseases, and an increase in the number of targeted countries (Liese and Schubert 2009). It has been estimated that 1.2 billion PZQ tablets will be needed annually to treat 400 million people in Africa for at least five years, at an annual cost of US$100 million (Utzinger et al. 2009). This sum could not be afforded easily within the endemic areas of the world without help from the developed countries. However, much less money would be required if alternative medicine(s) could be produced locally in appropriate financial and ecological frameworks.

Geographical implications

In many areas with high rates of schistosomiasis the local health systems are under-resourced (Amazigo et al. 2012) and subject to diverse disturbances that disrupt ecological equilibria and contexts, within which disease hosts or vectors and parasites breed, develop, and transmit the disease (Cable et al. 2017). Thus, they may strongly influence the emergence and proliferation of parasitic diseases, including schistosomiasis. It has been estimated that 97% of the infections are on the African continent (Steinmann et al. 2006), at least partly due to the lack (or paucity) of health systems, poverty and general neglect (Utzinger et al. 2011). Furthermore, 95% of all parasitic infections occur in the developing world, since it has the most conducive combinations of human behavior, anthropogenic disturbance and both climatic and physical conditions (Sattenspiel 2000). Notably, in endemic parts of the world schistosomiasis is intimately connected to the construction of infrastructure such as small, multipurpose dams and large hydroelectric dams for power production and irrigation systems (Utzinger et al. 2011). In the modern era, for example, the Aswan High Dam caused ecological changes that stimulated disease transmission (Malek 1975). Schistosomiasis remains the most important water-borne disease, and it was promoted by prevailing socio-ecological systems, since transmission is governed by unsafe human behavior (e.g. unprotected direct surface water contacts and open defecation) (Acka et al. 2010).

In Egypt, recent projects have been carried out in many regions to reclaim land from the desert for agriculture using water of the Nile River. This, together with the increased human activities in the reclaimed areas, has stimulated transmission of both S. mansoni and S. haematobium, manifested by the presence of infected B. truncatus and B. alexandrina, the intermediate host snails for the respective parasitic species, in these areas. Parts of the desert utilizing Nile water has wider spread of schistosomiasis (El-Kady et al. 2000). Schistosomiasis became a national burden and emerging as a major public health problem in the Egyptian reclaimed areas unless adequate control measures are taken (Abou-El-Naga 2018). There are also cases of human infection in American and European metropolitan areas, due to immigrations (Fuertes et al. 2010; Roure et al. 2017).

Medical implications

Hepatitis has been detected in 70% of surveyed schistosomiasis patients, and S. mansoni is one of the two major risk factors, together with viral hepatitis, for chronic liver disease and liver cirrhosis. Thus, millions of the world´s population live under constant risk of both schistosomiasis and hepatitis (Halim et al. 1999). Similarly, clinical history of urinary schistosomiasis is associated with significantly increased risk of bladder cancer (Bedwani et al. 1998). Furthermore, schistosomiasis can infect the children in endemic populations, and disease symptoms in children include anemia, liver fibrosis, immunity impairment, and severe physical and mental disorders (El Baz et al. 2003).

The free-swimming Schistosoma larvae penetrate the skin, causing rashes, erythema and itchy skin prior to fever, chills, coughm and muscle aches. As the parasite matures in the host veins (mesenteric or vesical), the symptoms change dramatically, and blood becomes visibly present in patients’ urine and stool (Kolářová et al. 2013; Nation et al. 2020). Under chronic conditions and if parasite eggs damage the organ in which they were deposited, the carrier can suffer from liver, kidney, and bladder complications. Advanced intestinal schistosomiasis is manifested with enlarged liver and spleen, fibrosis, and portal hypertension while symptoms of advanced uro-genital schistosomiasis include hydronephrosis and calcification of the bladder (Andrade 2009; Salas-Coronas et al. 2020).

Social implications

Advances in understanding Schistosoma epidemiology, and the greater availability of effective diagnosis and new tools have improved both current management and prospects for refining control of schistosomiasis. Nevertheless, infection and morbidity rates of the disease are still high, particularly in poor and otherwise disadvantaged populations. This disease of poverty has proved to be difficult to control for centuries (Utzinger et al. 2011). Despite prolonged mass antiparasitic drug therapy programs and other control measures, it has not been eradicated and continues to spread to new geographical areas (Siddiqui et al. 2011). Globally, WHO has estimated that about (600–779) million people are at risk of infection due to their exposure to contaminated water and 200–209 million people are infected with these parasites (Steinmann et al. 2006; WHO 2012). Schistosome infections require direct contact in water between the skin and the infective cercariae, thus sociocultural factors are strongly linked to infection rates, as illustrated in Fig. 2. In addition, recording and reporting of incidences, prevalence and death rates remain a challenge, and further efforts are needed to improve tracking the disease both nationally and globally. Accordingly, schistosomiasis is still considered one of the major healths, socio-economic and developmental challenges facing many of the world´s poorest countries.

Fig. 2
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Infection by schistosomes is strongly associated with social activities (washing clothes, bathing, etc.) in which people come into direct contact with freshwater inhabited by schistosomes’ intermediate host snails

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Strategies to eliminate schistosomiasis

There is an urgent need to increase global awareness and support endemic countries’ endeavors to develop appropriate methods to control the disease (Rollinson et al. 2013). As already mentioned, it is generally agreed that no single method will be sufficient to eliminate schistosomiasis; integrated approaches will be required due to its complexities (Mo et al. 2014). Application of molluscicides to reduce intermediate host snails populations is one of the most efficient methods for controlling the disease (Rapado et al. 2011). However, there are four major strategies for eradication: (1) treating infected individuals to reduce morbidity and mortality, and preventing the spread of Schistosoma parasite eggs, (2) providing communities with adequate, appropriate sanitation and accessible safe water to reduce environmental contamination and hence minimize the chances of miracidia transmission, (3) snail control to block the lifecycle of the parasite, and (4) health education (Fig. 3) (Chimbari 2012). To accelerate progress, a wider application of existing interventions combined with implementation of new methods in a manner tailored to the socio-ecological setting is required. In China, a comprehensive control strategy to reduce rates of S. japonicum transmission from humans and cattle to snails was evaluated from 2005 to 2007. The strategy included removing cattle from snail-infested areas, providing farmers with mechanical equipment, improving sanitation and implementing health-education programs in the endemic areas. This integrated strategy reportedly reduced S. japonicum infection in humans to less than 1% in an endemic area (Wang et al. 2009).

Fig. 3
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Strategies for schistosomiasis eradication

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Medical control of schistosomiasis by treating infected humans

A systematic search for chemotherapeutic drugs has been ongoing for several decades. The synthesis of PZQ in 1970 revolutionized the treatment and led to dramatic reductions in morbidity and mortality rates. PZQ is the only drug being used to treat human schistosomiasis on a large scale (Doenhoff et al. 2008; Mordvinov and Furman 2010), and is highly recommended in disease-control programs (Salvador-Recatalà and Greenberg 2012). The scope of therapeutic programs, as treatment with PZQ has largely been restricted to children attending school due to the lack of infrastructure and other logistical problems in many areas of the developing world (Siddiqui et al. 2011).

Although treatment of schistosomiasis in patients worldwide relies heavily on PZQ and the drug has thoroughly recognized efficacy against schistosomes (Keiser et al. 2010), evidence is now accumulating that PZQ cannot prevent re-infection, and may sometimes even exacerbate it (Chandiwana et al. 1991; Doenhoff et al. 2008). Moreover, PZQ resistance is emerging in endemic areas due to repeated use (Wang et al. 2012). Obviously, there is a need for new alternatives for treating schistosomiasis (Cioli et al. 2014; Bergquist et al. 2017). Important potential sources are plants, and already many have been tested and some showed relevant activities, especially members of the medicinal plants. Many of them have been already tested and some showed relevant activities, especially members of the plant families Euphorbiaceae, Annonaceae, Fabaceae Asteraceae, Asphodelaceae, and Asparagaceae (Tables 1, 2, 3, 4 and 5).

Table 4 Extracts with recognized larvicidal activity
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Table 5 Compounds with antischistosomasis of water larvacidal activity isolated from higher plant
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Strategic controls of schistosomiasis by eliminating intermediate host-snails

Schistosoma parasites, like other parasitic helminths, can survive in their hosts for a long time, but the intermediate host is the weakest link in the transmission cycle. Thus, molluscicides are widely used as experimental models in programs to investigate the disease by killing the intermediate host snails (mollusks) (Wang et al. 2018), thereby disrupting the parasite’s lifecycle and stopping transmission to people in contact with water in high-risk areas (Birley 1991).

Synthetic molluscicides

The major synthetic molluscicides thatare currently used to control the snail vectors are metaldehyde, niclosamide, carbamate, organophosphate, and synthetic pyrethroids (Singh et al. 2010). Niclosamide is one of the most widely used synthetic molluscicides at present. However, it is highly toxic towards non-target organisms, including fish, and it is also ecologically destructive (He et al. 2017). Nevertheless, it is one of the most important molluscicides approved by WHO due to the lack of robust alternatives (He et al. 2017). It is most active against O. hupensis snails with an LC50 of 0.12 µg/ml and LC90 of 0.98 µg/ml after 24 h (Chen et al. 2007) but it kills amphibians and fish if used in effective concentrations. There are also several chemical molluscicides (e.g. copper sulfate, calcium cyanamide, chlorinated lime and carbamate derivatives). However, they are environmentally hazardous, and snails develop resistance to them (Bilia et al. 2000b).

Available molluscicides are also costly, which poses major problem for low-income countries where schistosomiasis is widely distributed. Despite all recent research and development current synthetic molluscicides also raise serious environmental concerns and threats to both human health and income (particularly in areas where fishing is a major source of food and income) due to their lack of specificity (Andrews et al. 1982; He et al. 2017). Thus, identifying or developing more selective molluscicidal herbal preparations that do not have adverse effects (or at least acceptably weak effects) in non-target aquatic organisms and are biodegradable remains a high priority (El-Sherbini et al. 2009).

Plant molluscicides

Several thousand synthetic compounds have been tested for their ability to control host snails but none of of them was proven to be as entirely satisfactory as yet. Therefore, natural sources of novel agents came into play an are considered now as attractive alterantives to seek for novel drug leads (Ribeiro et al. 2021; Xing et al. 2021). Primary target sources are medicinal plants because they are generally a rich source of renewable bioactive organic chemicals, and they may grow well in endemic areas, providing income for local farmers. Furthermore, plant derived molluscicides may have several advantages like low costs, high target specificity, water solubility, high biodegradability, and low toxicity towards normal organs in the human hots (Singh et al. 2010).

Since 1982, the potential utility of more than 150 plant species for controlling freshwater snails has been tested. Numerous groups of compounds plant-derived compounds were toxic to target organisms at acceptable doses, ranging from < 1 to 100 µg/ml (Singh et al. 2010). The molluscicidal activity of plant extracts and often their active compounds have been reported (Tables 1 and 2). Commonly identified active compounds belong to saponins, alkaloids, terpenoids and tannins (Fig. 4). The plant extracts evaluated against the intermediate host (snails and larvae of Schistosoma) are listed in Table 4. These include, for instance, methanol and aqueous extracts of Jatropha curcas L. (Euphorbiaceae) on snails transmitting S. mansoni and S. haematobium (Rug and Ruppel 2000). Different parts were traditionally used as antimicrobial agents. The plant had traditional uses as antimicrobial agents. Plant species known to be rich in bioactive molluscidal compounds are presented in Tables 2 and 5. Tannins are particularly suitable for snail control because tannin-containing plants are not only widely distributed but tannins can be also relatively easily isolated (Al-Sayed et al. 2014). The highest contents of molluscicidal agents have been found in members of Euphorbiaceae followed by Annonaceae, Mimosaceae, Polygonaceae, Verbenaceae and Caesalpinaceae families, the active compounds of a number of plants are presented in (Fig. 4). More extensive efforts are warranted to isolate and identify the remaining unknown compounds from other plants, that could meet all the desirable criteria of molluscicides.

Fig. 4
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The most bioactive of natural compounds against snails based on a review of literature: Fla, flavonoids; Ter, Terpenes; Alk, alkaloids; Ste, steroids; Sap, saponins; Cat, catechine; Tan, tannins; Car, carbohydrates; Ace, acetogenine; Ess, essential oils; Pro, proteins; ND, not defined

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Classes of compounds used as plant molluscicides

Saponins

Saponins comprise a structurally diverse class of triterpenes, based on triterpenoids often in the form of glycosides. They occur in plant species and have been also isolated from marine organisms (Challinor and De Voss 2013). Saponins derive their name from the soapwort plant, genus Saponaria (Caryophyllaceae). The triterpene skeletons of saponins are formed from the C30 precursor oxidosqualene. They are diverse, and decorated with different functional groups in different plant species (Challinor and De Voss 2013). They have hemolytic properties, toxic effects on most cold-blooded animals and proven molluscicidal activity (Francis et al. 2002; Sparg et al. 2004).

Triterpenoids and saponins are widespread in nature. The most active molluscicidal saponin compounds have an oleanolic acid-based aglycone and trisaccharide sugar moiety (Mølgaard et al. 2000). This is consistent with our recent finding that asparagalin A (Fig. 5) (1), a triterpene saponin from the Egyptian species Asparagus stipularis Forssk., suppresses S. mansoni egg-laying. Shoots and roots of this plant used in folk medicine as diuretic for curing jaundice, liver ailments, against bilharzias (El-Seedi et al. 2012). Sometimes molluscicidal compounds are formed by an enzymatic reaction during extraction of plants, for instance if Phytolacca dodecandra L'Hér. berries are crushed with water (Parkhurst et al. 1989).

Fig. 5
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A novel anti-schistosomiasis triterpene glycoside (Asparagalin A) (1)

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The desert tree Balanites aegyptiaca (L.) Delile (common name Higleeg) (Suleiman 2015) has a well-known molluscicidal activity. It was the first plant reported for the control of schistosomiasis owing to its saponins content (Marston and Hostettmann 1985). The fruits of this plant were used as remedy to eradicate intestinal parasites. This plant species is traditionally (Table 3) used in treatment of malaria and is apparently suitable for vector control (Chothani and Vaghasiya 2011).

Pulsatilla chinensis (Bunge) Regel displayed potent molluscicidal activity against O. hupensis, attributable to the presence of the active triterpenoid saponins. The plant roots are widely used in traditional Chinese medicine as remedies for amebiasis, malaria, vaginal trichomoniasis and bacterial infections. Treatment with a sub-lethal concentration reportedly caused significant inhibition of acetyl cholinesterase (AHE), alanine transaminase (ALT), and alkaline phosphatase (ALP) activities in the liver and the cephalopodium of O. hupensis (Chen et al. 2012).

Extracts of Calendula officinalis L. and Ammi majus L. (common name, Khilla sheitani) have molluscicidal activity against Bullinus truncates and B. Alexandria (less strongly). The recorded LC50 and LC90 values indicated that C. officinalis L. is more toxic to both snails where A. majus, and Bullinus. truncatus snails are more sensitive to the extracts of both plants than B. alexandrina. Prolonged exposure to sub-lethal concentrations of A. majus L. affected the egg-laying and survival of both snails. In addition, treatment with sub-lethal doses of extracts of both plants clearly inhibited transaminase activity, diminished the total protein content, and markedly increased total lipid contents in both snails hemolymph (Rawi et al. 1996). The activity of A. majus L. is thought to be due to saponins, and furocoumarins, although the effect seems to be highly snail species-dependent (Marston and Hostettmann 1985; Rawi et al. 1996).

Phytolacca dodecandra L'Hér. is one of the most active molluscicidal plants, and thus has been widely studied. Its activity was initially reported by Lemma`s group (Lemma 1965, 1970) and the presence of an active saponin named lemmatoxin was demonstrated (Parkhurst et al. 1974). Aqueous extracts of the dried berries contain up to 25% saponins (Treyvaud et al. 2000) which were stable in water for two days at room temperature (Mølgaard et al. 2000). Some isolated saponins are lethal to snails at very low concentrations. However, a major disadvantage of using saponins as molluscicides is that they are also generally lethal to fish compared to flavonoids and other phenolics that are generally less toxic to non-target organisms (Wei et al. 2002).

Glycoalkaloids

Several glycoalkaloids (Fig. 6) identified from Solanum species are molluscicidal. Extracts of S. elaegnifolium Cav. berries, and S. sodomaeum Dunal leaves and seeds reveal molluscicidal activity against Bu. truncates, the intermediate host of S. haematobium (Table 2) (Bekkouche et al. 2000). In addition, S. sisymbriifolium Lam. fruits are active against the snails, the active fractions contain the steroidal alkaloids solamargine (Fig. 7) (2) and β-solamarine (Bagalwa et al. 2010), but solamargine is the most effective of these compounds, due to its specific sugar substitution (Miranda et al. 2012). Solamargine (containing a chacotriose sugar chain moiety) is also more active than solasonine, (containing a solatriose sugar chain moiety) against adult S. mansoni worms (Miranda et al. 2012).

Fig. 6
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Structures of mollusicicidal bioactive compounds

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Fig. 7
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Solamargine, a glucoalkaloid containing a chacotriose sugar chain moiety with molluscicidal activity (2)

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Phorbol esters

Phorbol (Fig. 8) (3) was initially isolated in 1934 as a hydrolysis product of Croton tiglium L. vegetable oil (Flaschenträger, v. Wolffersdorff 1934; Abegaz and Kinfe 2020), and its structure was subsequently elucidated by Hecker and colleagues (Hecker 1967). Phorbol esters are diterpenes, which are, among others, major constituents of Jatropha curcas L. oil. They exhibit molluscicidal activity against aquatic snails (Liu et al. 1997). Some of the phorbol esters are mutagenic and thus not suited as a molluscicidal medicine (Liu et al. 1997).

Fig. 8
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Chemical structure of phorbol (3)

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Phorbol esters (and anthraquinone) are also the most bioactive compounds tested against miracidia and cercaria (Fig. 9). There have been few attempts to isolate bioactive water larvicidal compounds; however, more extensive investigations are warranted.

Fig. 9
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Lifecycle stages of Schistosoma targeted by natural compounds, and the most active plant families

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Neolignins

Neolignans are a group of dimeric phenylpropanoids that are formed in Myristicaceae and other primitive plant families (e.g. Piperaceae, Eucommiaceae and Lauraceae) by oxidative coupling of allyl and phenyl propanoids (Alves et al. 2002). The biological activities of neolignan derivatives have been investigated against fungi such as Microsporum canis, M. gypseum, Tricophyton mentagrophytes, T. rubrum, and Epidermophyton floccosum (Zacchino et al. 1997), bacteria (e.g. Staphylococcus aureus and Bacillus subtilis) (Pessini et al. 2003), and a panel of cancer cell lines (Siripong et al. 2006). A number of these compounds displayed anti-schistosomiasis activity (Mengarda et al. 2021), Structure–activity relationships of 18 synthetic neolignan derivatives have also been studied (Alves et al. 2002). Two neolignans isolated from the leaves of Virola surinamensis (Rol. ex Rottb.) Warb., virolin (Fig. 10) (4) and surinamensin have been active against S. mansoni (Alves et al. 1998).

Fig. 10
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Chemical structure of virolin (4)

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Latex with molluscicidal activity

Latex from Euphorbiaceae species has strong molluscicidal activity, particularly against aquatic snails (Bah et al. 2006). The crude latex of Euphorbia milii var. hislopii, the most powerful molluscicidal agent, has activity against the schistosomiasis-transmitting snails, B. glabrata and B. tenagophila, (Yadav and Jagannadham 2008). This could be due to the presence of triterpenes, flavonoids, macrolides, ingenol and a phorbol ester (Zani et al. 1993). The latex had stronger effects than the molluscicide niclosamide and was less less harmful to nontarget aquatic organisms (Oliveira‐Filho et al. 1999; dos Santos et al. 2007). It also affects the cercaeia and larval stage of Schistosoma species (De-Carvalho et al. 1998).

Latex of E. splendens Bojer ex Hook. is also a potent and specific molluscicide (LC90 < 1.5 µg/ml) against the vector snails (Schall et al. 1998). It did not show acute toxicity or mutagenic activity towards non-target species at the concentrations of 10–12 µg/ml (Schall et al. 1991). Attempts to identify the components responsible for the effects on snails showed that normal, processed, non-proteinaceous and proteinaceous fractions had molluscicidal activity, but the proteinaceous fraction containing alkaloids had the strongest physiological and lethal effects on fresh water snails (B. glabarata) (Yadav and Singh 2011).

Clinical trials for uses medicinal plants against schistosomiasis

70 schistosomiasis haematobium patients both sexes (aged > 15–60 years old) were treated with Mirazid at10 mg/Kg. The cure rate reached 91.9% after two months and 95.2% on the 3rd post-Mirazid treatment month (El Baz et al. 2003).

In total, 268 school children infected with S. mansoni were divided into three groups: PZQ (87), arachidonic acid (ARA, 91), and PZQ plus ARA (90). Over the course of three weeks, and for 15 days, PZQ 40 mg/kg/day, ARA 10 mg/kg/day, or PZQ combined with ARA (40 mg/kg on the first day of treatment, then 15 doses of ARA 10 mg/kg per day for 5 doses/week) were administrated. In children with light and heavy infections, PZQ and ARA together evoked cure rates of 83% and 78%, respectively. ARA, like PZQ, induced moderate cure rates (50% and 60%, respectively) in school children with light infection and modest cure rates (21% and 20%, respectively) in school children with high infection. Taken together, combination of PZQ and ARA might be useful for treatment of children with schistosomiasis in high-endemicity regions (Barakat et al. 2015).

Conclusion

Schistosomiasis is a major neglected tropical disease with high public health impact. It is difficult to control the disease due to the complex life cycle of the parasite and its wide distribution in tropical and subtropical areas where health and sanitation services are poorly developed. Field control currently relies mostly on some synthetic compounds, which are costly, especially for the low-income regions where the disease is endemic. Since 1981 more than 150 plant species have been tested for molluscicidal activity, and more than 60 natural molluscicidal compounds have been isolated. Preliminary results are encouraging but further investigations are needed to bring more significant progress to a to a large-scale application in the field, including rigorous pharmaceutical validation, particularly to assess candidate compounds’ specificity. More screening of natural sources is also needed, with particular emphasis on structure–activity relationships and action mechanisms. Saponins, for example, specifically block homeostatic circuits.

More research is also needed to discover and identify new environmentally friendly molluscicides and larvicides of plant origin that are not toxic to non-target aquatic organisms. Establishment of a global database of the distribution of schistosomiasis vector snails is also necessary for large-scale application of plant molluscicides and optimization of control programs.

The present review here shows that nature offers a plethora of possibilities for improving schistosomiasis control. Production of locally growing plants with molluscicidal and/or anti-schistosome activities would be an attractive alternative, since they could provide abundant agents to interfere with multiple stages of the parasite’s lifecycle without imposing excessive financial burdens. Natural products are likely to be the strongest defense; myriads remain to be discovered.