An autophagic mechanism is involved in the 6-hydroxydopamine-induced neurotoxicity in vivo

作者：He, Xin; Yuan, Wei; Li, Zijian; Feng, Juan^*

来源：Toxicology Letters, 2017, 280: 29-40.

DOI：10.1016/j.toxlet.2017.08.006

• Autophagy
• Cysteine protease
• Parkinson's disease
• 6-hydroxydopamine
• Neurotoxicity

6-hydroxydopamine (6-OHDA) is one of the most common agents for modeling dopaminergic neuron degeneration in Parkinson's disease (PD). So far, the role of autophagy in 6-OHDA-induced neurotoxicity remains controversial and most evidence is collected from in vitro studies. In this study, we determined the role of autophagy activation in 6-OHDA-induced neurotoxicity in a rat model of PD. Following 6-OHDA treatment, we observed a concomitant activation of autophagy and apoptosis. To further explore the interaction between autophagy and apoptosis induced by 6-OHDA, autophagy inhibitor 3-methylademine (3-MA) or cysteine protease inhibitor Z-FA-fmk was applied. We found that both 3-MA and Z-FA-fmk could not only exert immediate protection against 6-OHDA-induced neuronal apoptosis, but also prevent dopaminergic neuron loss in the long-term, which was related to reduced autophagosome formation. Furthermore, by monitoring the sequential changes of mTOR-related signaling pathways, we found that reactive oxygen species (ROS)-mediated AKT/AMPK-mTOR signaling pathway participated in but was not the initial cause of autophagy activation by 6-OHDA. Collectively, our data suggest that 6-OHDA-induced autophagy activation contributes to its neurotoxicity and targeting autophagy activation or cysteine proteases could be promising for developing neuroprotective agents for PD.

• 出版日期2017-10-5
• 单位中国医科大学