Neurocysticercosis (NCC) is a parasitic infection caused by the larval stage of the pork tapeworm, Taenia solium. It is a major cause of neurological disease worldwide, particularly in less developed countries where pigs are raised as a food source in non-controlled free roaming environment added to the sale of uninspected pork meat (Garcia et al., 2003; Megha et al., 2020). The management of neurocysticercosis involves a combination of antiparasitic drugs, surgery, and symptomatic treatment (Garcia et al., 2003; White Jr et al., 2018).

Antiparasitic treatment is generally recommended for patients with viable parenchymal and extra-parenchymal NCC. This recommendation is based on evidence from placebo-controlled trials that demonstrated more rapid radiologic resolution and fewer recurrent seizures in patients treated with antiparasitic drugs (Pineda-Reyes & White, 2022). The decision to initiate antiparasitic therapy should be individualized and based on factors such as the number, location and viability of the parasites within the nervous system (Dixon et al. 2021; Pineda-Reyes & White, 2022). In addition to antiparasitic drugs and surgery, the management of NCC includes the use of corticosteroids to reduce inflammation and control symptoms. When the cysticerci are located within the ventricles or in the subarachnoid space, i.e. considered extra-parenchymal, there is an exacerbated inflammatory reaction to anti-parasitic treatment which requires higher levels of corticosteroids (Del Brutto 2020; Pineda-Reyes & White, 2022).

Traditionally, the NCC treatment is performed with albendazole and praziquantel isolated or in combination with close monitoring for hepatoxicity, leucopenia, pancytopenia and allergic reactions (White Jr et al., 2018; Zhao et al., 2023). The effectiveness of the current NCC programs is only partially achieved. Compared to 40% of patients who receive no treatment, 60%–70% of cysts resolve after just one course of antiparasitic medication. Unfortunately, the percentage of patients without viable brain cysts is just 30%–40%. Only patients with active illness are advised to take antiparasitic medications. The number, size, location, and developmental stage of the cysts, the surrounding inflammatory edema, any clinical symptoms or signs, and potential treatment risk factors all affect dosage and length of treatment. While the effectiveness of steroids in reducing inflammation has been extensively established, it is important to note that because of their immunosuppressive qualities, their use may contribute to individuals with extraparenchymal NCC not responding to cysticidal medication (Fogang et al., 2015; Toledo et al., 2018; Del Brutto 2020). Therefore, our research group has been studying alternative therapeutic approaches to NCC treatment.

The inflammation observed in the brain tissue after the parasite`s degeneration and death are an important pathogenic mechanism associated to NCC clinical symptoms (Pineda-Reyes & White, 2022) and related to the severe NCC`s clinical manifestations such as epilepsy and seizures (Herrick et al. 2018). The literature suggest that corticosteroids are the mainstay of treatment for inflammation in NCC, but they can cause side effects (Nash et al., 2011; Anand et al., 2019; Hamamoto Filho et al., 2021). Therefore, there is the need for the development of alternative therapeutical approaches to treat NCC in order to associate the anti-helminthic and anti-inflammatory effects.

Oxfendazole is a broad-spectrum anti-helminthic drug and has been recommended against lungworms and enteric and tissue dwelling helminths (An et al., 2019; Dixon et al., 2021). This drug has been reported to present a longer plasma half-life than albendazole indicating that it may sustain effective concentrations in the human organism for a longer period of time (Gokbulut et al., 2007; An et al., 2019; Gonzalez et al., 2019). Oxfendazole showed significant action against the tissue stages of Taenia solium (cysticercosis) in various preclinical trials carried out in pigs, even with just one oral dose (Gonzalez et al. 1997). This drug has been showed to be effective against muscle and cerebral cysts in pigs although there was not a complete clearance of the cysts after treatment (Sikasunge et al., 2008; Mkupasi et al. 2013). This drug is a benzimidazole derivative, similar do albendazole, and is capable of inhibiting the tubulin formation within the parasitic cells and impairs the fumaric reductase, inducing protein catabolism and gluconegoenesis in the parasites, contributing to its death (Morgan et al. 1993; Correia et al. 2022). However, there is no description of the histopathologic effect of oxfendazole on the parasite and on the host-parasite interface.

Nitazoxanide is a broad-spectrum drug that has been shown to be effective against protozoans such as Entamoeba histolytica, Giardia intestinalis, Cryptosporidium sp, Trichomonas vaginalis (Miyamoto and Eckman 2015; Gupta et al., 2022), enteric and tissue dwelling helminths such as Taenia sp, Hymenolepis nana, Echinococcus multilcularis (Stettler et al., 2003; White 2004); viruses and bacteria such as Helicobacter pylori, Clostridium dificcilie, Hepatitis B, Sars-Cov2 amongst others (Nelson et al., 2017; Guevara and Cogdill 2020; Bharti et al., 2021, Al-Kuraishy et al., 2022). In protozoans this drug induces cell swelling, distorted cell shape, and plasma membrane damage (Cedillo-Rivera et al., 2002), while in nematodes it impairs a glutamate-gated chloride ion channel (Somvanshi et al., 2014) and against cestodes it induces several morphological alterations (Stettler et al. 2003). It has been demonstrated that it affects the pyruvate-ferredoxin oxidoreductase enzyme impairing the energetic metabolism of parasites (Bharti et al. 2021). Also, it has been reported that nitazoxanide combines synergistically with other anti-helminthic drugs such as benzimidazole derivatives (Somvanshi et al 2014) which indicates that it is a good candidate as repurposed drug for NCC treatment.

Experimental NCC is performed with the intracranial inoculation of Taenia crassiceps cysticerci in BALB/c mice and is a valid model to study several aspects of NCC host-parasite interaction and the parasite`s responses to different drugs (Matos-Silva et al. 2012, Sampaio et al. 2020, Santana et al. 2023). This experimental model has been useful to show that the combination of benzimidazole derivatives such as albendazole with antiparasitic drugs as nitazoxanide and ivermectin present an anti-inflammatory effect and is capable of inducing the parasite`s degradation (Sampaio et al. 2020, Santana et al. 2023).

Therefore, the aim of this study was to determine the histopathologic aspects of experimental NCC after in vivo treatment with the combination of oxfendazole and nitazoxanide.