TY - JOUR
T1 - Activation of autophagic flux and the Nrf2/ARE signaling pathway by hydrogen sulfide protects against acrylonitrile-induced neurotoxicity in primary rat astrocytes
AU - Yang, Bobo
AU - Bai, Yu
AU - Yin, Changsheng
AU - Qian, Hai
AU - Xing, Guangwei
AU - Wang, Suhua
AU - Li, Fang
AU - Bian, Jinsong
AU - Aschner, Michael
AU - Lu, Rongzhu
N1 - Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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.
KW - Acrylonitrile
KW - Astrocyte
KW - Autophagy
KW - Hydrogen sulfide
KW - Nrf2
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85046491235&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046491235&partnerID=8YFLogxK
U2 - 10.1007/s00204-018-2208-x
DO - 10.1007/s00204-018-2208-x
M3 - Article
C2 - 29725710
AN - SCOPUS:85046491235
SN - 0340-5761
VL - 92
SP - 2093
EP - 2108
JO - Archives of Toxicology
JF - Archives of Toxicology
IS - 6
ER -