title: Anti-parkinsonian effects of Nurr1 activator in ubiquitin-proteasome system impairment induced animal model of Parkinson's disease.
abstract: Nurr1 is a member of the nuclear receptor superfamily and is a potential susceptibility gene for Parkinson's disease (PD). Several lines of studies in vitro and in vivo reported that defects in the Nurr1 gene cause nigrostriatal neuronal deficiency as seen in PD. In the present study, we used a a synthetic low molecular weight Nurr1 activator which increases the transcription of Nurr1 to investigate whether it has anti-parkinsonian effects against nigrostriatal neuronal degeneration induced by proteasome inhibitor lactacystin. Adult C57BL/6 mice were treated orally with the Nurr1 activator and an inactive structural analog as a control at a dose of 10mg/kg per day, starting 3 days before microinjection of proteasome inhibitor lactacystin into the medial forebrain bundle and the treatment continued for a total of 4 weeks. Animal behavior tests, and pathological and biochemical examinations were performed to determine the anti-parkinsonian effects of the Nurr1 activator. We found that treatment with the Nurr1 activator significantly improved rotarod performance, attenuated dopamine neuron loss and nigrostriatal dopamine reduction, increased expression of Nurr1, dopamine transporter and vesicular monoamine transporter 2, and alleviated microglial activation in the substantia nigra of lactacystin-lesioned mice. These results suggest that the Nurr1 activator may become an innovative strategy for the treatment of PD.
authors.affiliation: Department of Neurosurgery, Provincial hospital affiliated to Shandong University, Jinan 250021, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xuping
authors.initials: X
authors.lastname: Li
authors.forename: Wen-jie
authors.initials: WJ
authors.lastname: Xie
authors.forename: Houzhen
authors.initials: H
authors.lastname: Tuo
authors.forename: Samuel
authors.initials: S
authors.lastname: Hintermann
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
mesh_terms: D000111:Acetylcysteine / Q000009:adverse effects / Q000031:analogs & derivatives; D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000009:adverse effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation; D050493:Vesicular Monoamine Transport Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; C493453:Slc18a2 protein, mouse; C493215:Slc6a3 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; C067713:lactacystin; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine; D000111:Acetylcysteine