Autophagy activation alleviates nonylphenol-induced apoptosis in cultured cortical neurons

作者：Li, Siyao; Jiang, Zhixin; Chai, Wenjie; Xu, Yuanyuan; Wang, Yi^*

来源：Neurochemistry International, 2019, 122: 73-84.

DOI：10.1016/j.neuint.2018.11.009

• Nonylphenol
• Apoptosis
• Autophagy
• Primary cortical neurons

Emerging evidence indicates that nonylphenol (NP), a widely diffused and stable environmental contaminant, causes damage to the central nervous system (CNS). Although NP could cross the blood-brain barrier (BBB) and accumulate in key brain regions, little is known about the direct effects of NP on neurons. In this study, we aimed to investigate the direct effects of NP exposure on induction of apoptosis and autophagy in primary cortical neurons. Results showed that exposure to NP decreased the cell viability in a concentration-dependent manner, The exposure led to both the increase of TUNEL-positive neurons and the activation of caspase-3. Increased levels of endoplasmic reticulum (ER) stress-related proteins, GRP78, CHOP, ATF4, and casepase-12, were observed in neurons exposed to NP. At the same time, the exposure decreased Bcl-2/Bax ratio and mitochondrial transmembrane potential, and increased the release of Cytochrome-C. In addition, NP exposure enhanced LC3-II conversion, decreased levels of SQSTM1/p62, and increased levels of Beclin-1 and LAMP2. NP exposure also reduced the protein levels of p-mTOR, and did not change the levels of total mTOR. Furthermore, to investigate the role of autophagy in NP-induced apoptosis, both the autophagy inhibitor chloroquine (CQ) and the autophagy inducer rapamycin (RAP) were applied to modulate autophagy activation in primary cortical neurons. The inhibition of autophagy caused by CQ enhanced NP-induced apoptosis; conversely, RAP-induced autophagy remarkably suppressed it. In conclusion, our findings demonstrate that NP exposure induced apoptosis with a concomitant increase of autophagic flux in primary cortical neurons, which supports the idea that this potential neurotoxin has direct effects of on neurons. Both ER stress and mitochondrial pathways may be involved in NP-induced apoptosis in neurons. Furthermore, our results also suggest that autophagy activation might be a protective strategy to ameliorate NP-induced apoptosis in neurons.

• 出版日期2019-1
• 单位中国医科大学