GABA attenuates neurotoxicity of zinc oxide nanoparticles due to oxidative stress via DAF-16/FoxO and SKN-1/Nrf2 pathways

Abstract

Zinc oxide nanoparticles (ZnO-NPs) are one of the most widely used metal oxide nanomaterials. The increased use of ZnO-NPs has exacerbated environmental pollution and raised the risk of neurological disorders in organisms through food chains, and it is urgent to look for detoxification strategies. γ-aminobutyric acid (GABA) is an inhibitory neurotransmitter that has been shown to have anxiolytic, anti-aging and inhibitory effects on nervous system excitability. However, there are few reports on the prevention and control of the toxicity of nano-metal ions by GABA. In zebrafish, ZnO-NPs exposure led to increased mortality and behavioral abnormalities of larva, which could be moderated by GABA intervention. Similar results were investigated in Caenorhabditis elegans, showing lifespan extension, abnormal locomotor frequency and behavior recovery when worms fed with GABA under ZnO-NPs exposure. Moreover, GABA enhanced antioxidant enzyme activities by upregulating the expression of antioxidant-related genes and thus scavenged excessive O2−. In the case of ZnO-NPs exposure, inhibition of nuclear translocation of DAF-16 and SKN-1 was restored by GABA. Meanwhile, the protective effect of GABA was blocked in daf-16 (−) and skn-1 (−) mutant, suggesting that DAF-16/FoxO and SKN-1/Nrf2 pathways is the key targets of GABA. This study provides a new solution for the application of GABA and mitigation of metal nanoparticle neurotoxicity.