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Neurotoxicity-Based Toxicometabolomics of N‑Ethyl Pentedrone Using Zebrafish as an In Vivo Model
Alexandre B Godoi1,2, Leonardo C Rodrigues1,2, Matheus F Alves3,4
1Campinas Poison Control Center, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-888, SP, Brazil.
ACS Omega
|November 3, 2025
Summary
New psychoactive substance N-ethyl pentedrone (NEP) causes neurotoxicity by altering neurotransmitter function and energy metabolism. Zebrafish studies reveal NEP
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- New psychoactive substances (NPS), especially synthetic cathinones like N-ethyl pentedrone (NEP), pose public health risks due to recreational use.
- The metabolism and neurobiological effects of NEP are not well understood, necessitating further investigation.
- Understanding NEP's toxicological profile is crucial for addressing potential health hazards associated with its use.
Purpose of the Study:
- To investigate the metabolism of N-ethyl pentedrone (NEP) in a zebrafish model.
- To elucidate the neurotoxicological effects of NEP exposure on the central nervous system.
- To identify NEP metabolites and understand their impact on neurochemical pathways.
Main Methods:
- Utilized the Zebrafish Water Tank protocol as an alternative model for toxicological evaluation.
- Employed liquid chromatography-high-resolution mass spectrometry (LC-HRMS) to identify NEP metabolites in exposure water and zebrafish brain tissue.
- Conducted untargeted toxicometabolomics to analyze adverse events in the central nervous system.
Main Results:
- Identified NEP metabolism via N-dealkylation, beta-ketone reduction, hydroxylation, and O-glucuronidation, with 3 metabolites in water and 7 in brain tissue.
- Toxicometabolomics revealed significant alterations in six metabolites, including upregulated propionylcarnitine, l-kynurenine, adenylyl(3'-5')-cytidine, and cytidine.
- Observed neurochemical changes suggest disruptions in neurotransmitter biosynthesis, energy metabolism, lipid metabolism, and oxidative stress responses.
Conclusions:
- NEP exposure induces neurotoxicity through disruptions in key neurochemical pathways, including neurotransmission and energy metabolism.
- Alterations in lipid metabolism and mitochondrial function contribute to the observed neurotoxic effects of NEP.
- The study validates the utility of zebrafish as a model for assessing the pharmacokinetics and toxicodynamics of NPS.
