EXPOSURE TO IBOGAINE DURING DEVELOPMENT INDUCES CARDIAC EDEMA, BRADYCARDIA, AND HYPERACTIVITY IN ZEBRAFISH (DANIO RERIO) EMBRYO-LARVAE

Resumo

INTRODUCTION: Ibogaine (IBG) is a hallucinogenic alkaloid traditionally used for religious purposes. Recently, its therapeutic use has been investigated due to its antiaddictive and neuroplastic effects. However, there are concerns about its cardiotoxicity, as fatalities have been reported due to QT interval prolongation and consequent induction of severe arrhythmias. Additionally, its developmental neurotoxicity (DNT) is not well characterized, posing challenges for its clinical application. In this context, zebrafish has emerged as a vertebrate model that enables the assessment of developmental and behavioral changes relevant to translational research. OBJECTIVE: To assess whether exposure to ibogaine during development induces neuro- and cardiotoxicity in zebrafish embryo-larvae. MATERIALS AND METHODS: A toxicity screening was conducted using the Fish Acute Toxicity Test (FET) between 100 and 1000 ng/mL. These concentrations are a rough approximation based on the available pharmacokinetic data on the peak plasma concentration reported in humans after a single dose of ibogaine. At the end of the FET (96 hours post-fertilization – hpf), larval images were acquired and analyzed using the DanioScope (Noldus, Netherlands) software to determine larval and organ size. Tail coiling assays were conducted at 26 hpf to assess the induction of DNT between 100 and 1000 ng/mL. Heart rate was measured at 48 hpf to evaluate cardiotoxicity. The larval photomotor response assay was performed at 144 hpf to determine possible neuromotor impairments, and thigmotaxis was also assessed, both using the Zebrabox (Viewpoint, France) software. RESULTS AND CONCLUSION: IBG did not induce lethality or malformations between 100 and 1000 ng/mL; however, there was an increase in pericardial area at 500 and 1000 ng/mL. All tested concentrations induced embryonic hyperactivity and bradycardia in a dose-dependent fashion. IBG increased swimming distance and larval velocity in both light and dark cycles at 500 and 1000 ng/mL, and reduced the time spent in the periphery of the well (arena) while increasing exploratory behavior. Therefore, its clinical use is discouraged in individuals with heart conditions and in pregnant women due to its cardiotoxic and developmental neurotoxic effects.