Central and Peripheral Neurotoxic Effects of Ivermectin in Rats

Abstract

ABSTRACT. Ivermectin is considered a very safe drug; however, there are reports of toxic effects in particularly sensitive populations or due to accidental overdose. 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 and 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 min to 83.13  32.22 min; mean  SD). Ivermectin causes an increase in the tonus (EC 50 =50.18 M) and contraction amplitude (EC 50 =59.32 M) 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 GABAergic 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.

Screening for an ivermectin slow-release formulation suitable for malaria vector control

“…After implantation, the animals were checked daily for clinical signs of IVM toxicity such as sleepiness, ataxia and increase in tone [39]. Blood for IVM quantification was drawn weekly for the first 12 weeks, under sedation, from the marginal ear vein.…”

Involvement of Purinergic P2X4 Receptors in Alcohol Intake of High-Alcohol-Drinking (HAD) Rats

“…injection volume of 1 ml/kg of body weight, in doses ranging from 1.5-7.5 mg/kg (c.f. Trailovic and Nedeljkovic, 2011). The vehicle consisted of propylene glycol (Sigma-Aldrich Co. LLC, St. Louis, MO, USA) in sterile saline, at a concentration equivalent to that present in the highest ivermectin dose used for each experiment.…”

Novel cell-free high-throughput screening method for pharmacological tools targeting K + channels

“…G protein-independent activation of GIRK2 by ivermectin is interesting because this drug is used in the treatment of parasitic infections, and its major side effect is CNS depression (24,25). The mechanism of depression is thought to occur through activation of mammalian GABA and glycine receptor Cl − channels (24,(26)(27)(28).…”

“…The mechanism of depression is thought to occur through activation of mammalian GABA and glycine receptor Cl − channels (24,(26)(27)(28). However, direct activation of GIRK2 channels in the nervous system could equally contribute to this side effect.…”