Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling.
Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling.
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DOI：
10.1155/2018/4196961
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发表时间：
2018
影响因子：
3.1
通讯作者：
Spano P
中科院分区：
文献类型：
--
作者：
Collo G;Cavalleri L;Bono F;Mora C;Fedele S;Invernizzi RW;Gennarelli M;Piovani G;Kunath T;Millan MJ;Merlo Pich E;Spano P
抗帕金森罗匹尼罗和普拉克索是D3受体（D3R-）偏好多巴胺能（DA）激动剂，用作治疗难治性抑郁症（TRD）的辅助治疗药物。虽然确切的抗抑郁作用机制仍不确定，但已经提出了D3R在TRD中发生的神经可塑性受损恢复中的作用。由于D3R激动剂在人类DA神经元上高度表达，我们利用人诱导多能干细胞（hiPSCs）的翻译模型研究了罗匹尼罗和普拉克索对结构可塑性的影响。来自健康供体的两个hiPSC克隆分化为中脑DA神经元。罗匹尼罗和普拉克索在培养3天后产生了剂量依赖性的树突树突化和体大小增加，这种作用被选择性D3R拮抗剂SB277011-A和S33084以及mTOR通路激酶抑制剂LY294002和雷帕霉素拮抗。所有处理都能有效减弱d3r依赖性p70s6激酶磷酸化的增加。BDNF的免疫中和、TrkB受体的抑制和MEK-ERK信号的阻断同样阻止了罗匹尼罗诱导的结构可塑性，这表明BDNF和D3R信号通路之间存在关键的相互作用。来自两个hiPSC克隆的DA神经元获得的数据高度相似，这支持了它们在通过多巴胺能机制作用的药理药物表征方面的可靠性。
The antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impaired neuroplasticity occurring in TRD has been proposed. Since D3R agonists are highly expressed on DA neurons in humans, we studied the effect of ropinirole and pramipexole on structural plasticity using a translational model of human-inducible pluripotent stem cells (hiPSCs). Two hiPSC clones from healthy donors were differentiated into midbrain DA neurons. Ropinirole and pramipexole produced dose-dependent increases of dendritic arborization and soma size after 3 days of culture, effects antagonized by the selective D3R antagonists SB277011-A and S33084 and by the mTOR pathway kinase inhibitors LY294002 and rapamycin. All treatments were also effective in attenuating the D3R-dependent increase of p70S6-kinase phosphorylation. Immunoneutralisation of BDNF, inhibition of TrkB receptors, and blockade of MEK-ERK signaling likewise prevented ropinirole-induced structural plasticity, suggesting a critical interaction between BDNF and D3R signaling pathways. The highly similar profiles of data acquired with DA neurons derived from two hiPSC clones underpin their reliability for characterization of pharmacological agents acting via dopaminergic mechanisms.
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影响因子：
48
作者：
Barone, Paolo;Poewe, Werner;Weintraub, Daniel
通讯作者：
Weintraub, Daniel
影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
影响因子：
64.8
作者：
Kriks, Sonja;Shim, Jae-Won;Piao, Jinghua;Ganat, Yosif M.;Wakeman, Dustin R.;Xie, Zhong;Carrillo-Reid, Luis;Auyeung, Gordon;Antonacci, Chris;Buch, Amanda;Yang, Lichuan;Beal, M. Flint;Surmeier, D. James;Kordower, Jeffrey H.;Tabar, Viviane;Studer, Lorenz
通讯作者：
Studer, Lorenz
影响因子：
11
作者：
Bessa, J. M.;Ferreira, D.;Sousa, N.
通讯作者：
Sousa, N.
影响因子：
5
作者：
Breuer, Megan E.;Groenink, Lucianne;Olivier, Berend
通讯作者：
Olivier, Berend