Peroxisome proliferator-activated receptor-γ (PPARγ) agonist is neuroprotective and stimulates PGC-1α expression and CREB phosphorylation in human dopaminergic neurons
Peroxisome proliferator-activated receptor-γ (PPARγ) agonist is neuroprotective and stimulates PGC-1α expression and CREB phosphorylation in human dopaminergic neurons
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DOI：
10.1016/j.neuropharm.2015.11.020
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发表时间：
2016-03-01
影响因子：
4.7
通讯作者：
Lindholm, Dan
中科院分区：
文献类型：
--
作者：
Makela, Johanna;Tselykh, Timofey V.;Lindholm, Dan
线粒体功能障碍与几种神经退行性疾病如帕金森病（PD）有关。过氧化物酶体增殖物激活受体-γ共激活因子-1 α（PGC-1 α）是线粒体生物发生的主基因，已被证明在PD模型中具有神经保护作用。在这项工作中，我们研究了过氧化物酶体增殖物激活受体-γ（PPAR γ）的选择性激动剂N-（2-苯甲酰基苯基）-O-[2-（甲基-2-吡啶氨基）乙基]-L-酪氨酸水合物（GW 1929）的作用机制，在培养的人多巴胺能神经元。数据显示，GW 1929增加了人类多巴胺能神经元的活力，并保护它们免受H2 O2和线粒体毒素鱼藤酮诱导的氧化应激。神经元的弹性增强归因于线粒体抗氧化剂和PGC-1 α水平的增加。GW 1929处理进一步增加了人多巴胺能神经元中的细胞呼吸、线粒体生物发生和沉默调节蛋白-1（SIRT 1）表达。磷酸化的cAMP反应元件结合蛋白（CREB）也强烈增加GW 1929处理的细胞。这些结果共同表明，PPAR γ激动剂GW 1929影响人多巴胺能神经元中的CREB信号传导和PGC-1 α活性，从而有助于增加细胞活力。这支持了这样的观点，即作用于神经元中的PPAR γ-PGC-1 α信号传导的药物可能在PD中具有有益作用，并且也可能在其他脑部疾病中具有有益作用。(c)2015爱思唯尔有限公司版权所有。
Mitochondrial dysfunction has been linked to several neurodegenerative diseases such as Parkinson's disease (PD). Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) is a master gene for mitochondrial biogenesis and has been shown to be neuroprotective in models of PD. In this work we have studied the mechanisms by which peroxisome proliferator-activated receptor-gamma (PPAR gamma) selective agonist N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-L-tyrosine hydrate (GW1929) acts on human dopaminergic neurons in culture. Data showed that GW1929 increased the viability of human dopaminergic neurons and protected them against oxidative stress induced by H2O2 and the mitochondrial toxin Rotenone. The enhanced resilience of the neurons was attributed to increased levels of mitochondrial antioxidants and of PGC-1 alpha. GW1929 treatment further increased cell respiration, mitochondrial biogenesis and sirtuin-1 (SIRT1) expression in the human dopaminergic neurons. Phosphorylation of cAMP responsive element-binding protein (CREB) was also robustly increased in GW1929-treated cells. Together these results show that the PPAR gamma agonist GW1929 influences CREB signaling and PGC-1 alpha activities in the human dopaminergic neurons contributing to an increased cell viability. This supports the view that drugs acting on the PPAR gamma-PGC-1 alpha signaling in neurons may have beneficial effects in PD and possible also in other brain disorders. (c) 2015 Elsevier Ltd. All rights reserved.