An Inventory of Anthelmintic Plants across the Globe

A wide range of novelties and significant developments in the field of veterinary science to treat helminth parasites by using natural plant products have been assessed in recent years. To the best of our knowledge, to date, there has not been such a comprehensive review of 19 years of articles on the anthelmintic potential of plants against various types of helminths in different parts of the world. Therefore, the present study reviews the available information on a large number of medicinal plants and their pharmacological effects, which may facilitate the development of an effective management strategy against helminth parasites. An electronic search in four major databases (PubMed, Scopus, Web of Science, and Google Scholar) was performed for articles published between January 2003 and April 2022. Information about plant species, local name, family, distribution, plant tissue used, and target parasite species was tabulated. All relevant studies meeting the inclusion criteria were assessed, and 118 research articles were included. In total, 259 plant species were reviewed as a potential source of anthelmintic drugs. These plants can be used as a source of natural drugs to treat helminth infections in animals, and their use would potentially reduce economic losses and improve livestock production.


Introduction
Livestock production plays a key role in the economic development of a country. Helminthiasis caused by a helminth infection is a major constraint in global livestock production. The mortality and morbidity in animal populations owing to infections caused by parasitic helminths are rapidly increasing worldwide [1]. These parasitic worms are categorized into two major groups: roundworms (phylum Nematoda) and flatworms (phylum Platyhelminthes) [2]. Among these parasites, gastrointestinal parasites pose a serious threat to livestock production. In recent decades, continuous and intensive use of synthetic anthelmintics has been the only method to control gastrointestinal nematodes. However, resistance to all available anthelmintic drug classes has been reported in livestock species. Resistance to an anthelmintic drug is often observed within a few years of introduction of   Echinococcus granulosus (protoscolex)

Haemonchus contortus
In vitro High activity for adulticidal and egg hatching inhibition [119] Polyphenols

Caenorhabditis elegans
In vitro and in vivo Inhibition of larval migration [120] Phenolic compounds Gastrointestinal nematodes In vitro In vivo Highest nematode motility (100%) in the higher concentrations of methanolic extract (50 mg/mL) [60] Presence of saponin, alkaloids, flavonoids, and tannins

Haemonchus contortus
In vitro High mortality rate [121] Presence of eugenol and asarone Moniezia expansa In vitro 100 mg/mL concentration and the time taken for the paralysis of the parasite amounts to 66.3 ± 0.03 min and death was recorded after 93.2 ± 0.09 min [122] Proanthocyanidins and flavonoids Haemonchus contortus In vitro Larval migration inhibition and adult worms' motility inhibition [123] Essential oils

Neoechinorhynchus buttnerae, endoparasite of Colossoma macropomum
In vitro All essential oils showed 100% anthelmintic efficacy within 24 h [124] 100% mortality was observed in the group treated with 100 mg/mL of herbal complex

Effect of Plant Extracts in Drug-Resistant Helminths
Medicinal plant extracts have long been used against helminth parasites in humans and livestock; however, scientific support for their application and research on the characterization of active composites remains limited [123]. Numerous studies have investigated anthelmintic resistance, especially in small ruminants. Most studies have used the fecal egg count reduction test (FECRT), which is based on field management practices. Nevertheless, in vivo experiments on drug efficacy have been conducted in areas with high economic importance. Notably, sheep have been studied more extensively than other livestock species, and a broad spectrum of therapeutics have already been developed for sheep [126]. Molecular methods are promising strategies for in vivo and in vitro diagnosis of many infections and may prove to be effective in the detection of parasitic nematodes and anthelmintic resistance [127][128][129][130]. Gaining knowledge about the mechanisms of resistance will ultimately help to reduce anthelmintic drug resistance in parasites. The diagnosis of drug resistance associated with genomic changes using molecular techniques would help in avoiding unnecessary treatments and thus reduce health complications. However, the use of natural plant compounds has the potential to be a complementary control option that can reduce dependence on drug therapy and delay the development of resistance [127,129,131].
In general, many plant secondary metabolites including chalcones, coumarins, terpenoids, tannins, alkaloids, antioxidants, and flavonoids [132,133] possess anthelmintic and neurotoxic properties [134] and inhibit mitochondrial oxidative phosphorylation [135,136]. These plant-based compounds typically show higher biological activity than synthetic compounds [137]. In many parts of the world, plants have been used for many generations and are still being used to treat parasitic diseases [138]. The identification of novel compounds from plants as anthelmintics is an emerging field of research. According to a study, between 2000 and 2019, 40 patents were granted for natural-product-based nematicides divided into seven structural classes [139], but none of them have yet been commercialized. However, difficulties in determining the mechanism of action of the main active ingredients in plant extracts are among the main barriers for researchers.

Advantages and Disadvantages of Using Plants for Helminth Parasite Control
Limited information is available on gastrointestinal helminth infections in livestock, which remain a major constraint to livestock production worldwide. Nevertheless, a recent study suggests that anthelmintic plants can be used as a potential resource to improve livestock production [38]. The use of plants as anthelmintics has certain benefits over contemporary veterinary treatments, including affordability, lack of adverse effects, and easy accessibility.
Although most of the information available about the antiparasitic properties of medicinal plants is oral and lacked scientific validity until recently, there is now a growing number of controlled laboratory experiments aiming to confirm and quantify anthelmintic plant activity [24]. Plants can be used in the following two manners: 1. plant parts can be used to cure infected animals naturally or 2. plant extracts and concoctions can be tested both in vitro and in vivo for their anthelmintic potential. The advantages of using antiparasitic plants include effectiveness against species resistant to synthetic anthelmintic drugs, limited or no risk of resistance development, and environmentally friendly procedure [42]. A major drawback is that, to date, only a small number of anthelmintic compounds such as macrocyclic lactones, cyclic octadepsipeptides, benzimidazoles, and imidazothiazoles have been identified in plants after decades of research [65]. Another drawback is the inconsistency between in vitro and in vivo studies on the use of plants as anthelmintics, raising questions regarding their validity and reliability [67]. Additionally, neurological effects associated with the dosage and bioavailability of some medicinal plants need to be elucidated before their use. The choice of an appropriate host-parasite system is tricky in in vivo studies because caring for the animal models adequately is expensive, timeconsuming, and labor-intensive [100]. Other drawbacks include uncertainty about plant efficacy, nonspecific responses, irreproducible preparations, and potential negative consequences. An alternative strategy is to use plant secondary metabolites with anthelmintic activity [73]. Secondary metabolites exhibit various modes of action for anthelmintic activity. For example, tannins hinder the feeding process of parasites through forming complexes with parasite proteins or deactivating key enzymes [73]. Terpenes block the tyramine receptors of parasites, whereas alkaloids create unfavorable conditions in the host intestine by generating nitrated and free sugars [97,124]. However, it is important to conduct more studies on the underlying molecular mechanisms and adverse effects on the host to improve drug development.

Recommendations
An ideal anthelmintic agent should have a broad spectrum of action, a high treatment rate with a single therapeutic dose, low toxicity to the host, and cost-effectiveness. Most currently used synthetic drugs do not meet these requirements. Commonly used drugs have side effects such as nausea, drowsiness, and intestinal disorders. The development of resistance to existing drugs in parasites and the high cost of drugs have led researchers to explore novel anthelmintic effective agents. Ethnobotanical drugs are the source of easily available and effective anthelmintic agents for humans, especially in tropical and developing countries. Thus, people use various herbs or products derived from plants to treat helminth infections. Plants produce secondary metabolites with various ecophysiological functions, such as defense against pathogen attacks and protection against abiotic stresses. These metabolites have potential medicinal effects in humans and animals.

Conclusions and Future Perspectives
It is estimated that more than 2.5 billion people are affected with helminth parasites at some stage in their lives. Parasitic diseases remain the major reason of substantial economic loss owing to their impact on livestock health and unexpected deworming costs. According to the literature review, potential anthelmintic plants exhibit great diversity in terms of species and compounds. Nevertheless, initially, all anthelmintics are tested in livestock before being used for human therapy; thus, developments in veterinary anthelmintics could also lead to advancements in human therapy. In addition, studies on nutritional support and vaccination are also required to develop livestock with low parasite susceptibility.

Conflicts of Interest:
The authors declare no conflict of interest.