An autophagic mechanism is involved in the 6-hydroxydopamine-induced neurotoxicity in vivo.
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.
['He|Xin|X|', 'Yuan|Wei|W|', 'Li|Zijian|Z|', 'Feng|Juan|J|']
D055372:AMP-Activated Protein Kinases D000818:Animals D001343:Autophagy D001522:Behavior, Animal D001927:Brain Diseases D005786:Gene Expression Regulation D008297:Male D016627:Oxidopamine D051057:Proto-Oncogene Proteins c-akt D051381:Rats D017207:Rats, Sprague-Dawley D017382:Reactive Oxygen Species D058570:TOR Serine-Threonine Kinases
Neurotoxicity 6-hydroxydopamine Autophagy Cysteine protease Parkinson’s disease