Orobol derivatives and extracts from Cudrania tricuspidata fruits protect against 6-hydroxydomamine-induced neuronal cell death by enhancing proteasome activity and the ubiquitin/proteasome-dependent degradation of α-synuclein and synphilin-1

We investigated the neuroprotective effects of orobol derivatives and ethanol extracts from Cudrania tricuspidata fruits. Among the nine isolates from a 50% ethanol extract from Cudrania tricuspidata fruits (CTE50), orobol (OB), 6-prenylorobol (POB), and 6,8-diprenylorobol (DPOB) showed neuroprotective effects in 6-OHDA-induced SH-SY5Y cell death. In addition, CTE50 and the three orobol derivatives (OB, POB, and DPOB) attenuated the cleavage of caspase-3, caspase-9, and PARP and inhibited the excessive generation of ROS. Furthermore, it enhanced the 6-OHDA-induced dysfunction of proteasome activity and reduced the accumulation of ubiquitin conjugated-proteins and the polyubiquitination of α-synuclein and synphilin-1. The proteasome inhibitor MG132 blocked the neuroprotective effects and the enhanced proteasome activity produced by CTE50 and the three orobol derivatives. These results demonstrate that CTE50 and three orobol derivatives protect against 6-OHDA-induced neurotoxicity by enhancing the ubiquitin/proteasome-dependent degradation of α-synuclein and synphilin-1, suggesting that they might be possible candidates for the treatment of neurodegenerative diseases.