title: Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson's disease models.
abstract: 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 injured 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 dopaminergic neurons through decreasing α-synuclein (α-Syn) expression and the interaction between α-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 α-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 α-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.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China. Electronic address: baoxiuqi@imm.ac.cn.
authors.forename: Xiu-Qi
authors.initials: XQ
authors.lastname: Bao
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China. Electronic address: kxc1981@yeah.net.
authors.forename: Xiang-Chen
authors.initials: XC
authors.lastname: Kong
authors.affiliation: Department of Pharmacy, Liaoning Dianli Central Hospital, 68 Wenhua Road, Shenyang 110015, China. Electronic address: konglibing1990@126.com.
authors.forename: Li-Bing
authors.initials: LB
authors.lastname: Kong
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China. Electronic address: wuliangyu@imm.ac.cn.
authors.forename: Liang-Yu
authors.initials: LY
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China. Electronic address: sunhua@imm.ac.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China. Electronic address: danzhang@imm.ac.cn.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D044482:Benzeneacetamides / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy*; D010636:Phenols / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D044482:Benzeneacetamides; C000632146:Ddit4 protein, rat; D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D010636:Phenols; D012097:Repressor Proteins; D014157:Transcription Factors; D051844:alpha-Synuclein; C084439:squamosamide; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D051057:Proto-Oncogene Proteins c-akt; D001058:Apomorphine
keywords: 6-OHDA; 6-hydroxydopamine; Akt; Co-IP; Co-Immunoprecipitation; FLZ; PD; PI3K; Parkinson's disease; TH; Tyrosine hydroxylase; phosphoinositide-3-kinase; tyrosine hydroxylase; α-Syn; α-synuclein