Central and Peripheral Neurotoxic Effects of Ivermectin in Rats

Abstract

Ivermectin is considered a very safe drug, however there are reports of toxic effects in particularly sensitive populations or due to accidental over-dose. The aim of this study was (1) to further characterize the central and peripheral toxic effects of ivermectin in animals and (2) to determine possible therapeutic strategies for use in cases of ivermectin poisoning. We tested the effects of experimental doses of ivermectin previously reported to cause various intensities of CNS depression. However, in our study ivermectin at 2.5, 5.0, and 7.5 mg/kg i.v. did not produce visible CNS depression in rats, 10 mg/kg resulted in sleepiness and staggering 10 to 40 min after application, while a dose of 15 mg/kg caused CNS depression very similar to general anesthesia. Ivermectin dose-dependently potentiates thiopentone-induced sleeping time in rats. Flumazenil (0.2 mg/kg), the benzodiazepine antagonist did not affect the action of thiopentone, however, it significantly reduced sleeping time in rats treated with a combination of ivermectin (10 mg/kg) and thiopentone (25 mg/kg) (from 189.86 ± 45.28 to 83.13 ± 32.22 min; mean ± SD). Ivermectin causes an increase in tonus (EC₅₀=50.18 μM) and contraction amplitude (EC₅₀=59.32 μM) of isolated guinea pig ileum, very similar to GABA, but without the initial relaxation period. These effects are dose-dependent and sensitive to atropine. Our results confirm the central and peripheral GABA-ergic properties of ivermectin in mammals and also indicate involvement of the cholinergic system in its toxicity. In addition, the results suggest that flumazenil and atropine have potential clinical roles in the treatment of ivermectin toxicity.