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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Daidzein has neuroprotective effects through ligand-binding-independent PPARγ activation
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Daidzein has neuroprotective effects through ligand-binding-independent PPARγ activation

机译：大豆苷元通过不依赖配体结合的PPARγ激活而具有神经保护作用

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摘要

Phytoestrogens are a group of plant-derived compounds that include mainly isoflavones like daidzein. Phytoestrogens prevent neuronal damage and improve outcome in experimental stroke; however, the mechanisms of this neuroprotective action have not been fully elucidated. In this context, it has been postulated that phytoestrogens might activate the peroxisome proliferator-activated receptor-γ (PPARγ), which exerts neuroprotective effects in several settings. The aim of this study was to determine whether the phytoestrogen daidzein elicits beneficial actions in neuronal cells by mechanisms involving activation of PPARγ. Our results show that daidzein (0.05-5 μM) decreases cell death induced by exposure to oxygen-glucose deprivation (OGD) from rat cortical neurons and that improves synaptic function, in terms of increased synaptic vesicle recycling at nerve terminals, being both effects inhibited by the PPARγ antagonist T0070907 (1 μM). In addition, this phytoestrogen activated PPARγ in neuronal cultures, as shown by an increase in PPARγ transcriptional activity. Interestingly, these effects were not due to binding to the receptor ligand site, as shown by a TR-FRET PPARγ competitive binding assay. Conversely, daidzein increased PPARγ nuclear protein levels and decreased cytosolic ones, suggesting nuclear translocation. We have used the receptor antagonist (RE) fulvestrant to study the neuroprotective participation of daidzein via estrogen receptor and at least in our model, we have discarded this pathway. These results demonstrate that the phytoestrogen daidzein has cytoprotective properties in neurons, which are due to an increase in PPARγ activity not mediated by direct binding to the receptor ligand-binding domain but likely due to post-translational modifications affecting its subcellular location and not depending to the RE and it is not additive with the agonist rosiglitazone.
机译：植物雌激素是一组植物来源的化合物，主要包括异黄酮，如大豆苷元。植物雌激素可预防神经元损伤并改善实验性卒中的结果;但是，这种神经保护作用的机制尚未完全阐明。在这种情况下，已经假定植物雌激素可能会激活过氧化物酶体增殖物激活受体-γ（PPARγ），从而在几种情况下发挥神经保护作用。这项研究的目的是确定植物雌激素黄豆苷元是否通过涉及PPARγ激活的机制在神经元细胞中引发有益作用。我们的研究结果表明，大豆黄酮（0.05-5μM）减少了大鼠皮质神经元暴露于氧-葡萄糖剥夺（OGD）诱导的细胞死亡，并改善了神经末梢的突触小泡循环，从而改善了突触功能，两者均被抑制由PPARγ拮抗剂T0070907（1μM）提供。此外，这种植物雌激素在神经元培养物中激活了PPARγ，如PPARγ转录活性的增加所示。有趣的是，这些效应不是由于与受体配体位点的结合所致，正如TR-FRETPPARγ竞争结合试验所表明的。相反，黄豆苷元增加PPARγ核蛋白水平，降低胞质蛋白，提示核易位。我们已经使用受体拮抗剂（RE）氟维司群研究了大豆苷元通过雌激素受体的神经保护作用，至少在我们的模型中，我们已经放弃了该途径。这些结果表明，植物雌激素黄豆苷元在神经元中具有细胞保护特性，这是由于PPARγ活性的增加不是由直接结合至受体配体结合域介导的，而是可能是由于翻译后修饰影响了其亚细胞的位置，而不取决于RE，并且它与激动剂罗格列酮不相加。

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