Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication

Abstract

Acute organophosphorus (OP) intoxication is a worldwide clinical and public health problem. In addition to cholinergic crisis, neurodegeneration and brain damage are hallmarks of the severe form of this toxidrome. Recently, we generated a chemical model of severe acute OP intoxication in zebrafish that is characterized by altered head morphology and brain degeneration. The pathophysiological pathways resulting in brain toxicity in this model are similar to those described in humans. The aim of this study was to assess the predictive power of this zebrafish model by testing the effect of a panel of drugs that provide protection in mammalian models. The selected drugs included "standard therapy" drugs (atropine and pralidoxime), reversible acetylcholinesterase inhibitors (huperzine A, galantamine, physostigmine and pyridostigmine), N-methyl-d-aspartate (NMDA) receptor antagonists (MK-801 and memantine), dual-function NMDA receptor and acetylcholine receptor antagonists (caramiphen and benactyzine) and anti-inflammatory drugs (dexamethasone and ibuprofen). The effects of these drugs on zebrafish survival and the prevalence of abnormal head morphology in the larvae exposed to 4 µM chlorpyrifos oxon [1 × median lethal concentration (LC50)] were determined. Moreover, the neuroprotective effects of pralidoxime, memantine, caramiphen and dexamethasone at the gross morphological level were confirmed by histopathological and transcriptional analyses. Our results demonstrated that the zebrafish model for severe acute OP intoxication has a high predictive value and can be used to identify new compounds that provide neuroprotection against severe acute OP intoxication. © 2016, The Author(s). ; This work was supported in part by the US Army ERDC-IRO (W912HZ-13-BAA-01; D.R.), the NATO SfP project MD.SFPP 984777 (D.R.), the Portuguese Foundation for Science and Technology Grant SFRH/BPD/78342/2011 (Programme POPH—QREN through the Portuguese Ministry of Education and Science and the European Social Fund; M.F.) and the Spanish Government (CTM2014-51985-R; D.R., E.P, M.F.). We also are grateful to Dr. Martí Pumarola from the Departament de Medicina i Cirurgia Animals of the UAB for their valuable comments on neuropathology. ; Peer reviewed