Review criteria

Review of literature was sourced from books and original review and research articles published in English, preferably in the last 15 years or so, and indexed on PUBMED, SCOPUS, SCIRUS, INDEX COPERNICUS, CHEMICAL AND BIOLOGICAL ABSTRACTS, MEDLINE, EMBASE, EBSCO, DOAJ, and THOMSON REUTERS databases. Keywords used for search purposes included: Neurocysticercosis; pathology; drug targets; therapy; drugs; Taenia solium. The outcome of the results was reviewed to identify relevant articles.

Introduction: parasite life cycle

Neurocysticercosis is caused by cysticercus cellulosae, the larvae of the tapeworm T. solium (Fig. 1). Neurocysticercosis is often fatal, following complication in surgery to remove cysts from the brain; however, mostly, no clear estimate of the mortality rates is available (Chandy et al. 2015; Carabin et al. 2011). Humans and pigs are the two hosts in the parasite life cycle. Humans are the primary or definitive hosts harboring adult parasites in their small intestine, while pigs are the secondary or intermediate hosts harboring the larval stages. Humans harboring Taenia infection pass out eggs along with the feces. These eggs are ingested by pigs roaming in areas with poor orofecal hygiene, rampant in poor regions of the world. The eggs enter the bloodstream after crossing the intestinal wall. They develop into oncospheres and then into metacestodes in the tissues of the intermediate host, such as striated muscles. Metacestodes then mature into cysticerci, which are vesicles containing an invaginated scolex. When humans consume undercooked pork infected with these cysticerci, these find their way into the gastrointestinal tract (GIT), where they evaginate, adhere to the mucosa, and start maturing into adult worms. These adults soon start producing eggs which are excreted with human feces, thus completing the life cycle. The human tapeworm carrier serves as a source of infection for both humans and pigs (Fogang et al. 2015). Adult parasites or its larval stages can be found in the human intestine (Taeniasis), brain (neurocysticercosis, NCC), or muscles (Cysticercosis). As with other helminth species, the adult T. solium has a very high fecundity and fertility rate to ensure chances of perpetuation of life cycle and survival of species. For all these reasons, the tapeworm carrier is the main target of control interventions (Fogang et al. 2015).

Fig. 1
figure 1

Life cycle of Taenia solium cysticerci. Reproduced from the Centers for Disease Control and Prevention. Cysticercosis. Atlanta, GA: Centers for Disease Control and Prevention. Available from http://www.cdc.gov/parasites/cysticercosis/biology.html

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Disease status in the Indian context

The epidemiology of the disease in the Indian scenario is not sufficiently detailed due to a lack of systematic population-based studies. All conditions and markers for the transmission of T. solium taeniasis are prevalent in India (Prasad et al. 2008). Systematic population-based studies are scarce in most parts of the country; hence, it is difficult to estimate the actual disease burden in India. However, as per recent CT and MRI reports, the incidence of NCC is astonishingly high in India, especially among the meat-eating poorer sections of the society with either no treatment or having a treatment gap of >90 %. In India, being a geographically, ethnically, and culturally diverse country, the estimation and monitoring of the disease incidence and burden is somewhat difficult. Consequently, there are wide differences in the frequency and reporting of cysticercosis in India (Fig. 2).

Fig. 2
figure 2

Geographical distribution and incidence of cysticercosis and Taenia solium taeniasis in India. Reproduced from Prasad et al. (2008)

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Cysticercosis seems to be widely endemic in North India, especially in the states of Bihar, Uttar Pradesh, and Punjab. A recent study on a rural pig farming community of Mohanlalganj block, Lucknow district of Uttar Pradesh, has reported the incidence of taeniasis at 18.6 % (Prasad et al. 2007). Incidence of the disease is quite low in Kerala, which is attributed to the high literacy rate, predominantly vegetarian community, and the high hygiene standard. The prevalence is low in Jammu and Kashmir, too, because of the predominant Muslim population which abstains from consuming pork due to religious reasons. As cysticercosis is a manageable, controllable, preventable, and eradicable disease, apt measures like community awareness about the disease etiology, education, mass awareness, improved methods of disease diagnosis, detection and treatment, medical facilities, as well as abstinence from buying and consuming cysticerci-infested pork can help in alleviating disease manifestation particularly in the endemic areas.

Epidemiology

A blood serum-based study from regions in and around Chandigarh on cysticercosis patients has reported that the majority of patients having anti-cysticercus antibodies belonged to the slum areas, and only 8 % of those who tested positive for the antibodies had a previous history of seizure (Khurana et al. 2006). Cysticercosis prevalence has been found to be low in Pondicherry using antigen and antibody detection methods (Parija et al. 2005). Rural parts of India have reported very wide treatment gaps, most probably due to the reasons cited above and the lack of proper medical facilities (Prasad et al. 2009).

Cysticercosis is also widely present among swine in India. The Mohanlalganj area in Lucknow, where pig rearing is prevalent, has reported a high incidence of cysticercosis (26 %) in swine, with more than 40 % of them having NCC (Prasad et al. 2002).

Pathological symptoms

NCC has been found to account for more than one-third of adult-onset epilepsy cases (Singh et al. 2013). The clinical and pathological symptoms and patterns of the disease are varied, depending on the number, size, and location of the cysticerci in the brain. In almost 50 % of the cases, NCC has been found to be asymptomatic (Winkler and Richter 2015). Usually, live cysticerci do not exhibit any appreciable symptoms in the central nervous system (CNS; Kramer et al. 1989). On the other hand, host immune reaction to dead/degenerating cysticerci has serious consequences, viz., focal encephalitis, edema, and vasculitis. Symptomatic manifestations of the disease include epileptic seizures and recurrent headaches if the cysts are lodged in the brain parenchyma (parenchymal NCC). Increased intracranial pressure, meningeal signs, stature and walk abnormalities, and anomalous behavior constitute the other clinically observed symptoms (Carabin et al. 2011; Garcia et al. 2014; Leon et al. 2015). On the other hand, cysts may also lodge in the extraparenchymal spaces of the brain, such as the ventricular system or subarachnoid space, leading to acute intracranial pressure and blockage of cerebrospinal fluid (CSF) flow, causing hydrocephalus (extraparenchymal NCC). Cranial nerve palsies and spinal infarction are some other symptoms related to NCC.

Conventional diagnosis: limitations and drawbacks

Excision biopsy

Biopsy is usually achieved by excision of the subcutaneous cysticerci, which are found in 4–25 % of patients with NCC. However, radiologic and serologic tests are required for confirmation of diagnosis, unless biopsy of a CNS lesion is possible (Carlton et al. 1997).

Neuroimaging

The disease is commonly diagnosed with CT and MRI. With the advent of CT and MRI, the contribution of NCC in seizure disorders has significantly increased (Rajshekhar et al. 2006). However, neither MRI nor CT is fully specific and reliable and may even predict suboptimal values, especially in endemic settings. Moreover, CT and MRI often miss out thin-walled cysts and require dedicated, skilled, and specialized personnel. Last but not the least, these are not cost-effective techniques and cannot be afforded by poor socioeconomic sections of the society on a routine basis.

Blood/serum-based immune-diagnostic methods

Due to limited access to expensive neuroimaging diagnosis by the poor sections of the society, serological tests are the most commonly preferred and reliable tests for NCC diagnosis in India. The enzyme-linked immunoelectrotransfer blot (EITB) assay uses affinity purified glycoprotein antigens to detect antibodies to T. solium (Tsang et al. 1989). This test has almost 100 % specificity. However, a major drawback of the method is its low sensitivity (50–60 %), especially in patients with a single intracranial cysticercus. Thus, EITB often gives false negative results in patients with NCC. Additionally, antibodies might be present as a result of Taenia infection in muscles or adipose of patients, and present or past infections without any brain involvement might also give false positive results, thus lowering the specificity of the test. Ito et al. (1998) have developed an enzyme-linked immunosorbent assay (ELISA) using cysticercus antigens purified by isoelectric focusing. The test, though having a high sensitivity and specificity for diagnostic purposes, has not been adopted widely because of the time and cost needed to purify antigens. Thus, antibody-based detection tests suffer from low cost effectiveness, considerable cross-reactivity, and failure to differentiate between viable and non-viable infections (Lightowlers et al. 2016).

Antigen detection tests

A number of tests are in vogue for the detection of T. solium cyst antigens in pigs (Rodriguez-del-Rosal et al. 1989; Nguekam et al. 2003) and humans (Correa et al. 1989; Erhart et al. 2002). The commercially available antigen ELISA kit for T. solium known as apDia is highly specific for viable T. solium cysticerci. The flip side is that it is not used on a large scale because of its high price. Another antigen ELISA has also been described which tests positive with more than two viable cysts (Garcia et al. 2000). It has also been reported recently that people living in endemic areas of T. solium transmission transiently test positive for Taenia antigens and afterwards revert to testing negative due to incompletely established infection, leading to short-term antibody responses and temporary presence of circulating antigens before being cleared by the immune system.

CSF analysis

It may be an alternative to imaging and blood-based methods for diagnosis. However, the results may be compounded/confounded by the presence of tuberculosis, meningitis, and viral encephalitis, which closely resemble those of NCC.

Novel methods of diagnosis

The medical significance of tapeworm is not due to it causing taeniasis, which is more or less asymptomatic, but because of the pathological symptoms caused when humans become infected with the larval or metacestode stages of the parasite that encyst in the brain and spinal cord, causing NCC. Poor specificity of current methods for the diagnosis of NCC, particularly in endemic settings, has paved the way for the formulation of diagnostic criteria for NCC. The diagnostic criteria for NCC have been published, which employ objective, clinical, radiological, immunological, and epidemiological data (Del Brutto 2012; Fogang et al. 2015).

Fast imaging employing steady-state acquisition

Fast imaging employing steady-state acquisition (FIESTA) is the latest technological advancement in the field of MRI affording better image resolution of fluid-filled structures. FIESTA employs a T2 steady-state contrast approach to provide better resolution with high signal-to-noise ratio of fluid structures and tissues. In addition, the basic pulse sequence parameters, viz., repetition time (TR) and echo time (TE), are infinitesimally small, enabling very short acquisition times in comparison to fast spin echo. A further advantage is that the acquired images are capable of different projections (maximum intensity projection), 3D representation using data from all pixels (volume rendering), and also 3D navigation. Because of its enhanced resolution, detection of thin-walled cysts which are often missed by traditional MRI techniques and non-neuroradiologists can be done with greater accuracy.

Microscopic examination of feces for Taenia eggs

Though human feces can be examined microscopically for the presence of Taenia eggs, the technique is otherwise insensitive in that it cannot distinguish between different species of the genus (T. solium, Taenia saginata, and Taenia asiatica; Li et al. 2013; Jeon et al. 2013; Watts et al. 2014; Hall et al. 1981).

Coproantigen detection assays

Apart from eggs, other parasite-derived antigens and products can be used for the detection/diagnosis of NCC and/or tapeworm in general using coproantigen detection assays or CoproELISA. Allan et al. (1990) have designed the first coproantigen test for taeniasis. Though not species-specific, it had greater sensitivity than fecal examination for the presence of eggs (Allan et al. 1996). On the other hand, a coproantigen ELISA test devised by Guezala et al. (2009) can detect adult excretory–secretory (ES) antigens of Taenia and is able to differentiate between infection caused by T. solium and T. saginata (Guezala et al. 2009). Although the test has been found to be reproducible, there are no further reports referring to the application of this species-specific test for mass detection purposes (Allan et al. 1990). There is a need to generate awareness for this efficient method in community programs.

However, this method is not without its set of drawbacks, the greatest being the need for polyclonal antisera, which means the titer and thereby its antigen specificity would vary in every batch and in every replication of the test. The other disadvantage is the cost and availability of specialized reagents used in all coproantigen tests, which further limits its use as a mass detection method. Last but not the least, a recent report has found that coproantigen ELISA test is not sufficiently reliable until the tapeworms become mature or gravid (Tembo and Craig 2015). These limitations have to be taken into consideration.

Detection of specific antibody in serum

Human tapeworm infection evokes the formation of specific antibodies that can be readily detected in serum (Jenkins and Rickard 1985; Heath et al. 1985; Wilkins et al. 1999). Two cloned ES antigens, namely, rES33 and rES38, have been evaluated for the diagnosis of T. solium using EITB format (Levine et al. 2004, 2007). Promising results have been obtained with rES33, offering better discrimination of T. solium from T. saginata (Levine et al. 2007). However, some degree of cross-reactivity has been found among sera from patients with echinococcosis and schistosomiasis (Handali et al. 2010a, b). All in all, the serological test for detection of taeniasis developed by Levine et al. (2004) holds considerable promise, but positive cases need to be verified by some other means as specific antibodies tend to persist for some time even after subjects have been treated and no longer harbor any active infection. This needs to be verified.

DNA-based methods

A number of methods have been developed that can detect species-specific parasite DNA using PCR (Lightowlers et al. 2016). A major advantage of PCR-based methods is their applicability even to stool samples (coproPCR), as well as the identification of a greater number of infected cases than are diagnosed by microscopy alone. When combined with microscopy, coproPCR further improves diagnostic sensitivity (Yamasaki et al. 2004). A multiplex PCR has been developed using amplification of cytochrome c oxidase subunit I (cox1), which provides for species-specific diagnosis and has been tried in a study at the community level (Yamasaki et al. 2004). Praet et al. (2013) have developed a real-time multiplex PCR by using transcribed spacer 1 of the ribosomal RNA, while Mayta et al. (2008) have developed a nested PCR approach utilizing the Tso31 gene. The nested PCR approach has an edge over other PCR-based detection methods owing to its increased sensitivity when tested on stool samples despite having limitations of technical complexity and costliness with respect to implementation as a mass detection tool. Difficulty in parasite DNA extraction and the presence of enzyme inhibitors in stool are other serious drawbacks (Nunes et al. 2006). In order to meet these limitations, Nkouawa et al. (2010) have developed a loop-mediated isothermal amplification (LAMP) test. Low equipment requirement and the ability to differentiate between Taenia species are the major advantages of this technique (Nkouawa et al. 2012). The method has been applied to a field survey to amplify DNA extracted from proglottids technique (Nkouawa et al. 2012). The test seems to be effective even with minimal instrumentation, though its specificity needs to be validated further.

Treatment of NCC

While adult worms are more or less asymptomatic, living harmlessly in the intestine, it is the larval stages, especially the cysts, that can present with symptomatic pathologic symptoms often leading to serious life-threatening conditions by virtue of their spread to other body parts like the brain, muscles, or other organs like the liver. NCC is conventionally treated either through chemotherapy or surgical intervention depending on patient health and cyst location.

Surgery

It is done when cysts lodge in such areas of the brain as may cause CSF obstruction, leading to hydrocephalus. Surgery is also the preferred method to excise intraocular cysts as they may lead to blindness. Asymptomatic subcutaneous or intramuscular cysticerci do not require treatment.

Current drugs and drug targets for NCC treatment

The only widely used drugs to treat tapeworm cysts are benzimidazoles (Hemphill et al. 2010). However, due to their considerable toxicity, these drugs are administered at concentrations that inhibit the growth and reproduction of parasites rather than killing them (Brunetti and White 2012). Thus, novel targets and compound classes are urgently needed for disease prevention, control, and intervention that possess low toxicity as well as better efficacy even at low doses.

Symptomatic therapy

Corticosteroids

These are frequently employed to treat and alleviate NCC-related symptoms in patients. Dexamethasone at doses of 4.5–12 mg/day is the most common treatment strategy (García et al. 2002). Prednisone at 1 mg kg−1 day−1 is used as a substitute for dexamethasone for chronic cysticercosis. To control brain edema, which is a common occurrence in NCC, up to 32 mg of dexamethasone per day has to be administered (Del Brutto et al. 1993). Mannitol, at a dose of 2 g kg−1 day−1, is also used to relieve acute intracranial hypertension associated with NCC.

Antiepileptic drugs

Other treatment options to treat symptoms in NCC patients are antiepileptic drugs and analgesics. First-line antiepileptic drugs (AEDS) like phenytoin or carbamazepines are efficient in controlling seizures (Singhi et al. 2003). There is debate regarding the tenure of use of AEDS especially after an acute episode of seizure, which commonly happens due to the host immune system-mediated inflammation to degenerating cysticerci. However, it is advisable to continue with the treatment until the brain lesion gets resolved, as can be determined by neuroimaging. Most health care professionals prefer repeating MRI or CT scans after a gap of about 6 months or so to confirm full treatment, after which AED administration can be tapered off over a period of 12 weeks. In contrast, seizures in response to inactive or calcified parasites are unprovoked. In this case, treatment with AED should be continued until no episode of seizure has occurred for a period of about 2 years (Sinha and Sharma 2009).

Cestocidal therapy

Niclosamide (niclosan, fenasal)

It is a sparingly water-soluble halogenated salicylanilide and has been the first synthetic drug developed in 1959 against the adult parasite (Fig. 3). It has a good therapeutic index and low bioavailability, which works as an advantage since a systemic spread is not required (Gordana et al. 2014). Although the mode of action of niclosamide on cestodes is not completely known, it has been demonstrated that the drug interferes with parasite glucose uptake and alters the serotonin level in parasite tissues (Terenina et al. 1998). The drug is still in use as a first-line treatment against adult parasites. Interestingly, recently, it has been reported that niclosamide can also act as a potential anticancer agent (Li et al. 2014) by virtue of its inhibiting several signaling pathways, viz., Wnt/β-catenin, mTORC1, STAT3, NF-kB, and Notch, leading to arrest of cell cycle, cancer growth inhibition, and apoptosis, and it is a classical example of a repurposed drug. Contraindications are abdominal pain, anorexia, diarrhea, and sometimes skin rash.

Fig. 3
figure 3

Chemical structure of niclosamide

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Praziquantel (biltricide, cysticide, prazisan)

Introduced in 1972 by Bayer and Merck, praziquantel, an acylated isoquinoline-pyranzine, is still being used as a broad-spectrum antihelminthic against a number of intestinal cestodes (Fig. 4). It is also active against T. solium cysticerci in the brain, eye, and other tissues. There is a clearance of about 60–70 % of parenchymal cysts following a 15-day treatment at a dose of 50 mg kg−1 day−1 (Nash 2003; Sotelo et al. 1984, 1985). Recently, a single-day treatment regimen with praziquantel has been introduced, having the same result as long-term treatment (Corona et al. 1996; Del Brutto et al. 1999; López-Gómez et al. 2001; Pretel et al. 2000). The mode of action is currently not entirely understood, but research studies indicate that praziquantel increases membrane permeability to calcium ions, causing paralysis. The paralyzed parasite is dislodged from its site and enters into circulation, where it is killed by components of the host immune system, viz., phagocytes. There are still alternative mechanisms of action by which the drug exerts its effect, such as through focal disintegrations. Yet another hypothesized mechanism of action of praziquantel has been recently reported. The drug appears to block adenosine uptake in cultured worms, which leads to the death of the parasites due to the functional absence of de novo purine biosynthesis pathways in cestodes.

Fig. 4
figure 4

Chemical structure of praziquantel

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Common side effects are majorly due to the immune response evoked by the dying parasites and include such CNS symptoms as dizziness, headache, and malaise, GIT symptoms such as abdominal cramps, diarrhea, nausea, vomiting, and colitis, and such hypersensitivity symptoms as urticaria, rash, pruritus, and eosinophilia.

Albendazole (Albenza)

It is a broad-spectrum antihelminthic of the class benzimidazoles, also used for the control and treatment of NCC, and is found to be more effective than praziquantel (Sotelo et al. 1988a, b, 1990; Takayanagui and Jardim 1992; WHO/FAO/OIE 2005). Albendazole is poorly absorbed from the GIT due to its low aqueous solubility and rapidly metabolized to albendazole sulfoxide, which is responsible for its cestodicidal activity (Fig. 5). Earlier recommended to be administered at a dosage of 15 mg kg−1 day−1 for 1 month, the drug is now given as a 1-week course at the same dosage and has been found to be more effective than praziquantel (Garcia et al. 1997, 2004; Sotelo et al. 1988a, b).

Fig. 5
figure 5

Chemical structure of albendazole

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As an adulticidal, albendazole causes inhibition of cell division in the intestinal cells of the worm by binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules. As a result of the disintegration of the microtubular assembly, the glucose uptake is impaired in both adult and larval stages of the parasites, leading to exhaustion of their glycogen stores. This causes degeneration of the endoplasmic reticulum and mitochondria of the germinal layer and the subsequent release of lysosomes, leading to parasite death. Abdominal cramps, dizziness, headache, and alopecia are some of the associated side effects as a result of albendazole therapy.

Combination regimen

Combined administration of praziquantel and albendazole seems an attractive possibility as both exert a different mode of action on the parasite and praziquantel increases the bioavailability of albendazole sulfoxide when the two are given together (Cobo et al. 1998; Kern 2006; Garcia et al. 2011). However, this needs further validation in clinical trials as the available data are not sufficient to draw conclusions (Pawłowski et al. 2001; Bygott and Chiodini 2009).

Repurposed drugs

Owing to the high cost of drug discovery and development, high rates of failure of discovered and designed drugs in combinatorial and in vivo screening, as well as the time taken to develop novel drugs, drug repurposing circumvents these problems by finding new uses for compounds other than those they were initially intended to treat. Apart from the known broad-spectrum veterinary anthelmintics which continue to power alternative treatment regimens, a number of antimalarials, antibiotics, antiprotozoals, and anticancer agents also seem to have considerable efficacy as anti-parasitic agents and, as such, are detailed below.

Nitazoxanide (Alinia)

A derivative of niclosamide, it is primarily an antiprotozoal agent active against Cryptosporidium species and Giardia intestinalis and approved by the FDA in 2002 (Fig. 6). It belongs to the family thiazolides, a class of drugs which are synthetic nitrothiazolyl-salicylamide derivatives having anti-parasitic and antiviral activities (Sisson et al. 2002; Di Santo and Ehrisman 2013; Rossignol 2014). The drug is rapidly metabolized to nitazoxanide in humans (Sisson et al. 2002; Korba et al. 2008; Di Santo and Ehrisman 2013; Rossignol 2014). It has been shown that nitazoxanide is a noncompetitive inhibitor of enzyme pyruvate:ferredoxin/flavodoxin oxidoreductases of a number of bacteria and protozoan parasites and also one of the first agents that target the “activated cofactor” of an enzyme rather than its substrate or catalytic sites, a novel mechanism that may prove beneficial to combat rapidly emerging drug resistance to known agents (Hoffman et al. 2007). Its strong vermicidal activity makes it an attractive alternative to cases which do not show improvement to praziquantel or niclosamide treatment (Lateef et al. 2008).

Fig. 6
figure 6

Chemical structure of nitazoxanide

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Mepacrine/Quinacrine (Atrabine)

Mepacrine is mainly used as an antiprotozoal, antirheumatic, and an intrapleural sclerosing agent (Fig. 7). Mepacrine was approved as an antimalarial drug in the 1930s to prevent malaria (Baird 2011). It is an acridine derivative which has been replaced by chloroquine in recent times for antimalarial therapy. It is also approved for the treatment of giardiasis (an intestinal parasite; Canete et al. 2006) and has been found to be an inhibitor of phospholipase A2. Though the mechanism of action against protozoans is uncertain, it is thought to act against the protozoan’s cell membrane. It is a known inhibitor of histamine N-methyl transferase and NF-kB and activator of p53. Similarly, quinacrine has been evaluated for the treatment of niclosamide-tolerant Taenia infections (Gardner et al. 1996; Koul et al. 2000).

Fig. 7
figure 7

Chemical structure of quinacrine

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Tribendimidine

Tribendimidine, an amidantel derivative, has been found to be active against Onchocercus viverrini and Clonorchis sinensis liver fluke infections, which makes it a promising anthelmintic agent against cestodes (Fig. 8). The anticestodal potential of tribendimidine has been demonstrated in mice infected with Hymenolepis microstoma. A triple dose of 50 mg/kg tribendimidine, for three consecutive days, has been shown to reduce worm burden by more than 95 % (Kulke et al. 2012).

Fig. 8
figure 8

Chemical structure of tribendimidine

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Paromomycin (Humatin)

Paromomycin (Humatin) is an aminoglycoside antibiotic, active against Gram-negative and many Gram-positive bacteria (Fig. 9). It has been used for the treatment of amoebiasis and giardiasis. In India, it is being used as a licensed drug for the treatment of leishmaniasis (Davidson et al. 2009). The taenicidal activity of paromomycin was discovered accidently in 1960 during studies on amoebiasis treatments, when it was seen that co-infected patients shed segments of T. saginata (Salem and el-Allaf 1969). Paromomycin acts as a protein synthesis inhibitor in nonresistant cells by binding to 16S ribosomal RNA (Vicens and Westhof 2001).

Fig. 9
figure 9

Chemical structure of paromomycin

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Tamoxifen

Tamoxifen is a synthetic estrogen receptor modulator (Fig. 10) and a known anticancer drug against breast cancer. While working as an estrogen receptor antagonist in breast tissue, it exerts agonistic effects in other tissues (den Hollander et al. 2013). It has been shown that tamoxifen decreases parasite burden by 80 and 50 % in female and male mice, respectively, including reduced reproduction and loss of motility of parasites in vitro (Vargas-Villavicencio et al. 2007). Tamoxifen most likely binds to and interferes with some estrogen receptor-like proteins which are currently envisaged to play crucial roles in a number of critical physiological processes of the parasite (see below section on novel targets). Escobedo et al (2013) have also demonstrated the strong cysticidal and anti-taeniasis effects of tamoxifen on T. solium, which should be explored further in humans and cattle.

Fig. 10
figure 10

Chemical structure of tamoxifen

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Metrifonate (Trichlorfon)

Metrifonate is an organophosphorous compound that has been used as an insecticide and veterinary anthelmintic. In humans, it has been used for the treatment of schistosomiasis (Holmstedt et al. 1978). It is an irreversible inhibitor of enzyme acetylcholinesterase, and within the body, it is non-enzymatically activated into 2,2-dichlorovinyl dimethyl phosphate. About 75 % clearance of nodules and reduction in the size of nodules has been reported in persons suffering from heavy cutaneous cysticercosis infection after two treatment courses of metrifonate at 10 mg kg−1 day−1 for 6 days (Fig. 11). However, some adverse drug effects have been reported, which are relieved by the administration of atropine (Tschen et al. 1981).

Fig. 11
figure 11

Chemical structure of metrifonate

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Vaccination

Attempts have been made in the past few decades or so to develop effective vaccines and novel chemotherapeutic agents for the purpose of immunization of pigs and block transmission of T. solium. Though considerable progress has been made, there is still no ideal vaccine available for pig or human immunization. Extracellular proteins as well as cell surface antigens of the parasites are the most promising targets for vaccine and drug development. Since the oncosphere within the intermediate host (pig or human) is the first infective stage of the parasite to come in direct contact with the host immune system, it is usually the most important target for the design of new anti-parasitic agents. An antigen, termed TSOL18, for pig vaccination has so far been proven to be an effective immunogen in clinical trials, but still no further progress has been made in the area (Flisser et al. 2004; Gonzalez et al. 2005; Assana et al. 2002). The complex life cycle of the parasite, more or less asymptomatic nature of the disease in the primary host, and its ability to hide from/evade the host immune system make T. solium a poor candidate for vaccine development. Vaccination against T. solium does not, therefore, appears to be immunologically or logistically feasible at the present.

Limitations/drawbacks of currently used drugs

Current treatment for NCC with the above antihelminthic drugs has been reported more than 15 years ago, but effective clinical trials to establish the specific indications, definite doses, and duration of treatment are lacking (Kramer 1995). Recently, there has also been much debate on the usefulness and safety of anticysticercal treatment (Singh and Sander 2004). Anticysticercal therapy may increase or worsen cerebral edema and produce stroke, which may eventually lead to death. No vaccines or new drugs have either been discovered or are in pipeline for clinical trials, which necessitates the search for novel drug targets against this neglected disease.

Potential/novel drug targets

For reasons mentioned hereinabove, effective treatment for NCC and taeniasis warrants a search for novel drug targets. Recently, the genomes of four parasitic species of tapeworms have been completely sequenced and mapped (Tsai et al. 2013), viz., Echinococcus multilocularis, Echinococcus granulosus, T. solium, and the laboratory model H. microstoma. It has been found that tapeworms lack many genes and pathways that are otherwise ubiquitous in other animals, including 34 homeobox families. On the other hand, the presence of ever-renewing somatic stem cells accounts for the extreme regenerative capability, fecundity, and developmental plasticity of tapeworms. Additionally, tapeworms have specialized detoxification pathways, non-canonical heat shock proteins, and a more tailored proteome and metabolism that are finely tuned with those of their hosts (Tsai et al. 2013). The following may serve as promising drug targets in future studies on drug intervention in NCC.

MAP kinases and other protein kinases

The mitogen-activated protein kinase (MAPK) family regulates a host of cellular processes such as growth and reproduction. In parasites, the roles of MAPKs have been scarcely studied and therefore have been a focus of increasing and renewed attention (Krishna and Narang 2008). Interestingly, MAPKs are among the most evolutionarily conserved proteins from invertebrates to mammals (Tanoue et al. 2000; Levin-Salomon et al. 2009). It has been found that extracellular signal-regulated kinases (ERK 1/2) are involved in estrogen-dependent reproduction of the helminth parasites (Escobedo et al. 2010a, b). The role of ERK 1/2 in host–parasite interaction is still not clear (Escobedo et al. 2005), but an ERK-like protein has been demonstrated to be involved in host–parasite signaling and has the potential to be considered as a target for antihelminthic drug design.

Approximately 250 to 300 new protein kinases have been identified in genome sequencing and mapping of parasitic tapeworms (Tsai et al. 2013), and these can serve as potential targets because of their multiple roles in all major metabolic pathways of the parasite.

Parasite antioxidant system

Antioxidant enzymes are of paramount importance in the protection of parasites from host-generated oxidative stress (ROS) and are involved in a plethora of other important physiological functions. These enzymes are used by parasites for host immune evasion. The crystal structure of a recombinant T. solium Cu/Zn-SOD has been worked upon and was the first protein structure that was reported from this organism (González et al. 2002). Three antioxidant enzymes have been studied in T. solium, viz., cytosolic Cu, Zn superoxide dismutase (target of bencimidazoles), a 2-Cys peroxiredoxin, and two isoforms of glutathione transferase(s). These are experimentally known to protect immunized mice against cysticercosis. Most importantly, these enzymes are expressed and functionally present in all developmental and adult stages of the parasite. This suggests the very important role that antioxidant enzymes play in T. solium physiology and infection and can be exploited for the sake of novel drug development.

Proteases

In a study reported by Yan et al. (2014), about 197 novel proteases belonging to 37 families have been identified in T. solium through bioinformatic data mining and classified into aspartic, cysteine, serine, metallo-serine, and threonine proteases (Yan et al. 2014) depending upon the active site amino acid residue having proportions consistent with those of other organisms (Bos et al. 2009). This study is in contrast to only three putative proteases identified in T. solium to date (Li et al. 2006). These newly identified proteases may serve as potential targets for the development of new drugs as they are thought to play critical roles in the virulence, invasion/entry, migration of the parasite within the host, evasion/downregulation of host immune responses, as well as in the developmental biology of the parasite. This area warrants further investigation.

G-protein-coupled receptors

Since majority of the known antihelminthics target neural communication of the parasite, more than 60 putative G-protein-coupled receptors and 31 ligand-gated ion channels have been classified by Tsai et al. (2013). Praziquantel targets a voltage-gated calcium channel subunit and is quite effective in the adult parasite, but has low efficacy on the encysted stage because the said calcium channel subunit is not expressed in the larval stage (Marks and Maule 2010).

Acetylcholinesterases

These are yet other targets for drug design. These enzymes are inhibited by a known antimalarial mefloquine and have been found to reduce egg production in E. multilocularis (VanNassauw et al. 2008). However, acetylcholinesterases as a target to block transmission of the parasite have limited applicability because of their low expression in the developmental stages of the parasite.

Estrogen receptor-like proteins

It has been found recently that steroidal hormones have profound effects on the development of parasites Taenia crassiceps and T. solium (Escobedo et al. 2004, 2010a, b; Guadalupe et al. 2011; Vargas-Villavicencio et al. 2008) by suppressing the reproduction and viability of T. crassiceps metacestodes in a dose-dependent fashion (Escobedo et al. 2004; Vargas-Villavicencio et al. 2008), while 17-β-estradiol and progesterone have the opposite effects (Escobedo et al. 2004). Interestingly, tamoxifen (an estrogen receptor antagonist widely used in the treatment of estradiol-dependent breast cancers) has been found to exert a protective effect against T. crassiceps both in vitro and in vivo (Vargas-Villavicencio et al. 2007). Similarly, RU486, a progesterone antagonist, inhibits both scolex evagination and worm development induced by progesterone (Escobedo et al. 2010a, b). Despite the fact that there is a clear direct effect of steroid hormones on some parasites, their mechanism of action has still not been elucidated completely. In T. solium, sequences related to a progesterone receptor have been identified based on RT-PCR and Western blotting (Escobedo et al. 2010a, b), and a mRNA having sequence similarity to estrogen receptor has been demonstrated in the cysticerci of T. crassiceps (Escobedo et al. 2004). If steroidal hormone receptors do exist in Taenia cysticerci, then all estrogen receptor antagonists are expected to have a drastic effect on parasite transmission and development. Future studies could involve the evaluation of the cysticidal effect of tamoxifen in human parasite T. solium, which may contribute to the search and design of novel therapeutic agents for the control of cysticercosis in humans and livestock. Table 1 enlists the most promising targets in cestodes for the development of novel drugs and vaccines.

Table 1 Potential drug targets in cestode parasites (reproduced and modified from Tsai et al. 2013)
Full size table

Future challenges and solutions

NCC has been identified as a potentially eradicable disease by the Center for Disease Control and Prevention Working Group on Parasitic Diseases. The emphasis should be more on personalized therapy rather than that based on generalizations. More clinical trials and community-based programs are needed to study the control in transmission and propagation of the parasite by existing conventional drugs, especially in endemic regions of the world. There is ample scope for search and development of new drugs and alternate medicines for therapy. No vaccines or new drugs against cysticercosis are as such currently under trial, although some research groups have reported the success of a few proteins in the vaccination of porcine cysticercosis, but this needs rigorous studies and investigations.

Concluding remarks

In India, as public–private sector collaborations continue to enlarge and thrive, there is a possibility of undertaking a concerted and systematic research for combinatorial high-throughput screening of proposed chemical structures. Use of bioinformatics tools to predict structure–activity relationships between proposed compounds and their prospective targets can rev up investigations and save a lot of time and cost required for the development of novel drugs by conventional means. Translational research is the need of the hour in the area of neglected diseases in order to achieve medications that are accessible, affordable, and amenable to the poorer sections of the Indian society in particular and of the world in general.