Zebrafish behavioral response to ivermectin: insights into potential neurological risk

ABSTRACT

Ivermectin is a well-known and widely used anti-parasitic drug. Recently, in vitro data suggest anti-viral efficacy of the drug, albeit at much higher concentrations than currently approved. Despite warnings by several governing bodies, the (uncontrolled) human use of ivermectin has significantly increased during the COVID-19 epidemic. This study thus aimed to elucidate potential neurological risk of particularly the veterinary formulation of ivermectin in comparison to pure ivermectin. Zebrafish eggs (1hpf) and larvae (4dpf) were exposed to a range of concentrations of either pure ivermectin (IVM) or a veterinary formulation (V-IVM) for a period of 24 hours. Behavioral responses to both treatments were assessed at various timepoints using the pentylenetetrazol assay, the light-dark assay and a 5-day teratogenesis protocol. In addition, dissolution rates were calculated for both treatments. Acute responses of larvae at 4 - <5dpf was similar for both treatments – a transient hyperlocomotion was followed by a general hypolocomotion (ANOVA dose effect, P<0.01). Both IVM and V-IVM-treated larvae showed significant dose-dependent (ANOVA dose effect, P<0.0001) decreases in responsiveness to repeated light-dark transitions, which again was more pronounced in IVM. These effects were maintained after 24 hours of exposure. In contrast, when ivermectin was administered prior to establishment of the blood brain-barrier in the teratogenesis protocol, V-IVM treatment was linked to more severe activity decline on <5dpf. Differences in dissolution rates cannot account for these differences. In conclusion, current data suggest significantly higher neurological risk of a veterinary formulation of ivermectin under conditions of penetration across the blood brain-barrier.