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Prolonged DADLE exposure epigenetically promotes Bcl-2 expression and elicits neuroprotection in primary rat cortical neurons via the PI3K/Akt/NF-κB pathway.
Acta Pharmacologica Sinica ( IF 8.2 ) Pub Date : 2018-Oct-01 , DOI: 10.1038/aps.2018.7
Min Zhu , Ming Liu , Qi-lin Guo , Cui-qing Zhu , Jing-chun Guo

Both in vivo and in vitro studies have shown the beneficial effects of the delta-opioid receptor (DOR) on neurodegeneration in hypoxia/ischemia. We previously reported that DOR stimulation with [(D-Ala2, D-Leu5) enkephalin] (DADLE), a potent DOR agonist, for both a short (minutes) and long (days) time has notable protective effects against sodium azide (NaN3)-induced cell injury in primary cultured rat cortical neurons. We further demonstrated that short-term DADLE stimulation increased neuronal survival through the PKC-mitochondrial ERK pathway. However, the mechanisms underlying long-term neuroprotection by DADLE remain unclear. Here, we showed that DOR stimulation with DADLE (0.1 μmol/L) for 2 d selectively activates the PI3K/Akt/NF-κB pathway in NaN3-treated neurons; this activation increased Bcl-2 expression, attenuated Cyto c release and promoted neuronal survival. Further investigation revealed that sustained DADLE stimulation increased Bcl-2 expression by enhancing NF-κB binding to the Bcl-2 promoter and upregulating the histone acetylation levels of the Bcl-2 promoter. Our results demonstrate that prolonged DADLE exposure epigenetically promotes Bcl-2 expression and elicits neuroprotective effects in the NaN3 model via the PI3K/Akt/NF-κB pathway.

中文翻译:

长时间的DADLE暴露通过PI3K / Akt /NF-κB途径表观遗传地促进Bcl-2表达并引起原代大鼠皮层神经元的神经保护。

体内和体外研究均显示了δ-阿片受体(DOR)对缺氧/缺血性神经变性的有益作用。我们以前曾报道过,用强力DOR激动剂[(D-Ala2,D-Leu5)脑啡肽(DADLE)刺激DOR对短时间(几分钟)和长时间(天)都有明显的保护作用,以防止叠氮化钠(NaN 3诱导的大鼠原代培养皮层神经元细胞损伤。我们进一步证明,短期DADLE刺激可通过PKC-线粒体ERK途径提高神经元存活率。但是,尚不清楚DADLE对长期神经保护的潜在机制。在这里,我们表明用DADLE(0.1μmol/ L)进行DOR刺激2 d可以选择性激活NaN3处理的神经元中的PI3K / Akt /NF-κB途径;这种激活增加了Bcl-2的表达,减弱了Cyto c的释放并促进了神经元的存活。进一步的研究表明,持续的DADLE刺激可通过增强NF-κB与Bcl-2启动子的结合并上调Bcl-2启动子的组蛋白乙酰化水平来增加Bcl-2的表达。通过PI3K / Akt /NF-κB途径的3种模型。
更新日期:2018-05-24
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