Repositioning anthelmintics for the treatment of inflammatory-based pathological conditions

Abstract

Acute, uncontrolled and/or long-lasting inflammation causes a breakdown in immunological tolerance, leading to chronicity and contributing to a series of significant local or systemic tissue changes. Anti-inflammatory efficacy, fewer adverse effects, improved selectivity, and curative action are imminent issues for patients suffering from chronic inflammation-related pathologies. Then, we performed a complete and critical review about anthelmintics, discussing the main classes and the available preclinical evidence on repurposing to treat inflammation-based conditions. Despite low bioavailability, many benzimidazoles (albendazole and mebendazole), salicylanilides (niclosamide), macrocyclic lactones (avermectins), pyrazinoisoquinolones (praziquantel), thiazolides (nitazoxanide), piperazine derivatives, and imidazothiazoles (levamisole) indicate that repositioning is a promising strategy. They may represent a lower cost and time-saving course to expand anti-inflammatory options. Although mechanisms of action are not fully elucidated and well-delineated, in general, anthelmintics disrupt mitogen-activated protein kinases, the synthesis of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-12, and IFN-γ), the migration and infiltration of leukocytes, and decrease COX-2 expression, which impacts negatively on the release of prostanoids and leukotrienes. Moreover, some of them reduce nuclear accumulation of NF-κB (niclosamide, albendazole, and ivermectin), levels of nitric oxide (nitazoxanide and albendazole), and mucus, cytokines, and bronchoconstriction in experimental inflammatory pulmonary diseases (ivermectin and niclosamide). Considering the linking between cytokines, bradykinin, histamine, and nociceptors with algesia, anthelmintics also stand out for treating inflammatory pain disorders (ivermectin, niclosamide, nitazoxanide, mebendazole, levamisole), including for cancer-related pain status. There are obstacles, including the low bioavailability and the first-pass metabolism.

Keywords: Antinociceptive activity; Bioavailability; Hyperalgesia; Immunomodulatory effects; Pro-inflammatory cytokines.