Activation of autophagic flux and the Nrf2/ARE signaling pathway by hydrogen sulfide protects against acrylonitrile-induced neurotoxicity in primary rat astrocytes.

Abstract:

:Hydrogen sulfide (H2S), the third gasotransmitter, has been shown to act as a neuroprotective factor in numerous pathological processes; however, its underlying mechanism(s) of action remain unclear. It is widely accepted that activation of moderate autophagy and the Nrf2/ARE signaling pathway play important roles in the biological self-defense systems. In the present study, we investigated whether exogenous H2S protects against the cytotoxicity of acrylonitrile (AN), a neurotoxin, in primary rat astrocytes. We found that pretreatment for 1 h with sodium hydrosulfide (NaHS), a donor of H2S (200-800 µM), significantly attenuated the AN-induced decrease in cell viability, increase in lactate dehydrogenase release and morphological changes. Furthermore, NaHS significantly attenuated AN-induced oxidative stress by reducing reactive oxygen species (ROS) levels and increasing glutathione (GSH) concentration. Moreover, NaHS activated the autophagic flux, detectable as a change in autophagy-related proteins (Beclin-1, Atg5 and p62), the formation of acidic vesicular organelles and LC3B aggregation, confirmed by adenoviral expression of mRFP-GFP-LC3. Additionally, NaHS stimulated translocation of Nrf2 into the nucleus and increased expression of heme oxygenase-1 and γ-glutamylcysteine synthetase, downstream targets of Nrf2. Notably, the autophagy inhibitor 3-methyladenine and Beclin-1, or Nrf2-targeted siRNA, significantly attenuated the neuroprotective effects of NaHS against AN-induced neurotoxicity. In conclusion, we identified a crucial role of  autophagy and the Nrf2/ARE signaling pathway in H2S-mediated neuroprotection against AN-induced toxicity in primary rat astrocytes. Our findings provide novel insights into the mechanisms of H2S-mediated neuroprotection, and suggest that H2S-based donors may serve as potential new candidate drugs to treat AN-induced neurotoxicity.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Yang B,Bai Y,Yin C,Qian H,Xing G,Wang S,Li F,Bian J,Aschner M,Lu R

doi

10.1007/s00204-018-2208-x

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

2093-2108

issue

6

eissn

0340-5761

issn

1432-0738

pii

10.1007/s00204-018-2208-x

journal_volume

92

pub_type

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