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

Bobo Yang, Yu Bai, Changsheng Yin, Hai Qian, Guangwei Xing, Suhua Wang, Fang Li, Jinsong Bian, Michael Aschner, Rongzhu Lu

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Hydrogen sulfide (H 2 S), 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 H 2 S 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 H 2 S (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 H 2 S-mediated neuroprotection against AN-induced toxicity in primary rat astrocytes. Our findings provide novel insights into the mechanisms of H 2 S-mediated neuroprotection, and suggest that H 2 S-based donors may serve as potential new candidate drugs to treat AN-induced neurotoxicity.

Original languageEnglish (US)
Pages (from-to)2093-2108
Number of pages16
JournalArchives of Toxicology
Volume92
Issue number6
DOIs
StatePublished - Jun 1 2018

    Fingerprint

Keywords

  • Acrylonitrile
  • Astrocyte
  • Autophagy
  • Hydrogen sulfide
  • Nrf2
  • Oxidative stress

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this