Abstract
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.
Highlights
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
As described in mammalian models, the zebrafish model of acute ACR neurotoxicity is characterized by the depletion of the GSx stores and the covalent modification of some cysteine residues of selected proteins in the brain[16,17]
In this study we have analyzed the potential use of NAC as antidote against the systemic toxicity and neurotoxicity induced by ACR in adult zebrafish
Summary
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. ACR induces neurotoxicity by depleting cellular glutathione (GSx) levels and by forming Michael type adducts with functionally critical nucleophilic sulfhydryl thiolate groups on cysteine residues of proteins in the synaptic terminals[2,3]. We have developed an ACR acute neurotoxicity model in adult zebrafish by exposing animals to 0.75 mM ACR in water for 3 days[16] The characterization of this model showed that, as described in mammals, ACR depleted reduced glutathione (GSH) levels and formed adducts with selected cysteine residues of specific proteins in the brain[16,17]. We used the adult zebrafish model of ACR acute neurotoxicity to determine the suitability of NAC to protect the brain against ACR toxicity. We evaluated the ability of the drug to recover the depleted GSx stores and to scavenge ACR in the brain of ACR-exposed fish
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