Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
Mol Pharmacol. 2011 Dec;80(6):988-99. doi: 10.1124/mol.111.073262. Epub 2011 Aug 26.
Ethanol (ETOH) can cause apoptotic death of neurons by depleting GSH with an associated increase in oxidative stress. The current study illustrates a means to overcome this ETOH-induced neurotoxicity by enhancing GSH through boosting Nrf2, a transcription factor that controls GSH homeostasis. ETOH treatment caused a significant increase in Nrf2 protein, transcript expression, Nrf2-DNA binding activity, and expression of its transcriptional target, NQO1, in primary cortical neuron (PCNs). However, this increase in Nrf2 did not maintain GSH levels in response to ETOH, and apoptotic death still occurred. To elucidate this phenomenon, we silenced Nrf2 in neurons and found that ETOH-induced GSH depletion and the increase in superoxide levels were exacerbated. Furthermore, Nrf2 knockdown resulted in significantly increased (P < 0.05) caspase 3 activity and apoptosis. Adenovirus-mediated overexpression of Nrf2 prevented ETOH-induced depletion of GSH from the medium and high GSH subpopulations and prevented ETOH-related apoptotic death. These studies illustrate the importance of Nrf2-dependent maintenance of GSH homeostasis in cerebral cortical neurons in the defense against oxidative stress and apoptotic death elicited by ETOH exposure.
乙醇（ETOH）通过消耗 GSH 并伴随氧化应激增加，导致神经元凋亡性死亡。本研究通过增强 Nrf2 来克服这种 ETOH 诱导的神经毒性，Nrf2 是一种转录因子，控制 GSH 动态平衡。ETOH 处理导致原代皮质神经元（PCNs）中 Nrf2 蛋白、转录表达、Nrf2-DNA 结合活性和其转录靶标 NQO1 的表达显著增加。然而，这种 Nrf2 的增加并不能维持 GSH 水平以应对 ETOH，仍然会发生凋亡性死亡。为了阐明这一现象，我们在神经元中沉默了 Nrf2，发现 ETOH 诱导的 GSH 耗竭和超氧阴离子水平增加加剧。此外，Nrf2 敲低导致 caspase 3 活性和凋亡显著增加（P < 0.05）。腺病毒介导的 Nrf2 过表达可防止 ETOH 诱导的 GSH 从培养基和高 GSH 亚群中耗竭，并防止与 ETOH 相关的凋亡性死亡。这些研究表明，在防御由 ETOH 暴露引起的氧化应激和凋亡性死亡中，Nrf2 依赖的 GSH 动态平衡维持对大脑皮质神经元至关重要。
