Repeated Oral Administration of Ivermectin Belatedly Induces Toxicity and Disrupts the Locomotion and Neuropsychiatric Behavior in Rats

In 2020, the World Health Organization declared that COVID-19, caused by the SARS-CoV-2 virus, is a pandemic. This led to severe respiratory syndromes and overwhelmed hospital capacities alongside the widespread, yet unproven, use of drugs like ivermectin. Amidst growing concerns over the consequences of frequent ivermectin use, this study aims to examine its toxicological effects following repeated dosage in rats. Female Wistar rats received a daily dose of 12 mg/kg of ivermectin intragastrically for 5 days. Two groups were studied: one euthanized 24 h post the final dose (early protocol) and the other 14 days later (late protocol). The rats underwent tests for locomotion and anxiety- and depression-like behaviors. Additionally, blood and cortex samples were analyzed for acetylcholinesterase and Na+/K+-ATPase activities, oxidative stress levels, and liver and kidney function markers. The early protocol results showed decreased locomotion and increased signs of anxiety and depression in the rats, along with Na+/K+-ATPase inhibition and oxidative stress. In the late protocol, signs of persistent depression-like behavior and hyperlocomotion were observed, coupled with heightened oxidative stress, as indicated by increased reactive oxygen species and disrupted catalase activity. Moreover, the dual inhibition of acetylcholinesterase and Na+/K+-ATPase activities seems to underlie the behavioral alterations seen in the late protocol. The study also noted ivermectin's potential hepatotoxic effects, corroborating previous findings of elevated liver enzyme levels and severe drug-induced liver injury cases, as well as delayed neuropsychiatric and behavioral changes.