Therapeutic potential of N-acetylcysteine in acrylamide acute neurotoxicity in adult zebrafish

Melissa Faria, Eva Prats, Cristian Gómez-Canela, Chuan Yu Hsu, Mark A. Arick, Juliette Bedrossiantz, Manuel Orozco, Natàlia Garcia-Reyero, Tamar Ziv, Shani Ben-Lulu, Arie Admon, Leobardo Manuel Gómez-Oliván, Demetrio Raldúa

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Resum

Two essential key events in acrylamide (ACR) acute neurotoxicity are the formation of adducts with nucleophilic sulfhydryl groups on cysteine residues of selected proteins in the synaptic terminals and the depletion of the glutathione (GSx) stores in neural tissue. The use of N-acetylcysteine (NAC) has been recently proposed as a potential antidote against ACR neurotoxicity, as this chemical is not only a well-known precursor of the reduced form of glutathione (GSH), but also is an scavenger of soft electrophiles such as ACR. In this study, the suitability of 0.3 and 0.75 mM NAC to protect against the neurotoxic effect of 0.75 mM ACR has been tested in vivo in adult zebrafish. NAC provided only a mild to negligible protection against the changes induced by ACR in the motor function, behavior, transcriptome and proteome. The permeability of NAC to cross blood-brain barrier (BBB) was assessed, as well as the ACR-scavenging activity and the gamma-glutamyl-cysteine ligase (γ-GCL) and acylase I activities. The results show that ACR not only depletes GSx levels but also inhibits it synthesis from NAC/cysteine, having a dramatic effect over the glutathione system. Moreover, results indicate a very low NAC uptake to the brain, probably by a combination of low BBB permeability and high deacylation of NAC during the intestinal absorption. These results strongly suggest that the use of NAC is not indicated in ACR acute neurotoxicity treatment.

Idioma originalAnglès
Número d’article16467
RevistaScientific Reports
Volum9
Número1
DOIs
Estat de la publicacióPublicada - 1 de des. 2019

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