Regulation of redox-sensitive signaling pathways in rat primary astrocytes following acrolein exposure.
Regulation of redox-sensitive signaling pathways in rat primary astrocytes following acrolein exposure.
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DOI：
10.3233/jad-2011-102094
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发表时间：
2011
期刊：
影响因子：
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通讯作者：
T. N. Dang;M. Arseneault;C. Ramassamy
中科院分区：
文献类型：
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作者：
T. N. Dang;M. Arseneault;C. Ramassamy
脂质过氧化导致包括丙烯醛在内的许多副产物的形成。在阿尔茨海默病（AD）患者的大脑中，发现丙烯醛在脆弱区域升高。星形胶质细胞有助于多种神经功能，但丙烯醛在星形胶质细胞中的毒性仍然未知。使用大鼠原代星形胶质细胞，我们的结果表明丙烯醛从15 μM开始是有毒的。丙烯醛诱导谷胱甘肽（GSH）水平的双相效应，在处理30 min后耗竭，然后在暴露后24 h逐渐升高，同时诱导γ-谷氨酰半胱氨酸合酶（γ-GCS）的表达。蛋白质羰基水平显着较高的所有测试浓度的丙烯醛。我们进一步研究了丙烯醛对不同氧化还原敏感信号通路的调节作用。用20 μM丙烯醛处理30 min可激活NF-κB、Nrf 2和血红素加氧酶-1，而暴露24 h后，除NF-κB外，在亚毒性和毒性浓度的丙烯醛下观察到它们的诱导作用。Sirt-1也上调后24小时的丙烯醛暴露。处理30分钟后，丙烯醛还诱导p66 shc和ERK 1/2的磷酸化。我们的研究结果提供的证据表明，丙烯醛是一种有效的诱导剂的氧化还原敏感的途径在星形胶质细胞的差异调节后，短期或长期的暴露，以克服细胞死亡。考虑到星形胶质细胞在脑中的关键作用，这些结果表明丙烯醛可以通过引起星形胶质细胞的功能障碍或丧失来破坏神经元功能和突触稳态。
Lipid peroxidation leads to the formation of a number of by-products including acrolein. In brain from patients with Alzheimer's disease (AD), acrolein was found to be elevated in vulnerable regions. Astrocytes contribute to a variety of neuronal functions but the toxicity of acrolein in astroglial cells remains unknown. Using the rat primary astroglial cells, our results show that acrolein is toxic from 15 μM. Acrolein induced a biphasic effect on glutathione (GSH) levels with a depletion after 30 min of treatment followed by a progressive increase 24 hrs after exposure while the expression of γ-glutamyl-cysteine-synthase (γ-GCS) was induced. Protein carbonyls levels were significantly higher with all tested concentrations of acrolein. We have further investigated the effect of acrolein on the regulation of different redox-sensitive signaling pathways. A treatment with 20 μM of acrolein for 30 min activated NF-κB, Nrf2, and heme oxygenase-1 while after 24 hrs of exposure, their induction was observed with the subtoxic and toxic concentrations of acrolein except for NF-κB. Sirt-1 was also up-regulated after 24 hrs of exposure with acrolein. Acrolein also induced the phosphorylation of p66shc and of ERK1/2 after 30 min of treatment. Our results provide evidence that acrolein is a potent inducer of redox-sensitive pathways in astrocytes with a differential regulation after a short or a long term period of exposure to overcome cell death. Considering the crucial role of astrocytes in the brain, these results demonstrated that acrolein could disrupt neuronal functions and synaptic homeostasis by provoking dysfunctional or loss of astrocytes.