期刊
BRAIN RESEARCH
卷 1547, 期 -, 页码 49-57出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2013.12.026
关键词
FLZ; Parkinson's disease; Akt; alpha-synuclein; Tyrosine hydroxylase
资金
- National Natural Science Foundation of China [81000568, 81001430]
- Chinese National Basic Research Program [2011CB504105]
- Beijing NOVA Program [Z111102054511129]
- Beijing City Talents [2012D009008000005]
- Fundamental Research Funds for the Central Universities [2012S08]
- PUMC Youth Fund [2012319, 3332013111, 3332013128]
Parkinson's disease (PD) is a neurodegenerative disease affecting up to 80% of dopaminergic neurons in the nigrostriatal pathway. FLZ, a novel synthetic squamosamide derivative from a Chinese herb, has been shown to have neuroprotective effects in experimental PD models. In this study, we carried out a set of in vitro and in vivo experiments to address the neuroprotective effect of FLZ and related mechanism. The results showed that FLZ significantly improved motor dysfunction and dopaminergic neuronal loss of rats ihjured by 6-hydroxydopamine (6-OHDA). The beneficial effects of FLZ attributed to the elevation of dopaminergic neuron number, dopamine level and tyrosine hydroxylase (TH) activity. Mechanistic study showed that FLZ protected TH activity and doparninergic neurons through decreasing alpha-synuclein (alpha-Syn) expression and the interaction between alpha-Syn and TH. Further studies indicated the involvement of phosphoinositide 3-kinases (PI3K)/Akt signaling pathway in the protective effect of FLZ since it showed that blocking PI3K/Akt signaling pathway prevented the expression of a-Syn and attenuated the neuroprotection of FLZ. In addition, FLZ treatment reduced the expression of RTP801, an important protein involved in the pathogenesis of PD. Taken together, these results revealed that FLZ suppressed alpha-Syn expression and elevated TH activity in dopaminergic neuron through activating Akt survival pathway in 6-OHDA-induced PD models. The data also provided evidence that FLZ had potent neuroprotecive effects and might become a new promising agent for PD treatment. (C) 2013 Elsevier B.V. All rights reserved.
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