Department of Anesthesiology and Pain Medicine, Wonkwang University School of Medicine, 460 Iksandae-ro, Iksan, 570-749, Republic of Korea.
Amino Acids. 2013 Aug;45(2):393-401. doi: 10.1007/s00726-013-1518-9. Epub 2013 May 28.
Neuronal cell death caused by oxidative stress is common in a variety of neural diseases and can be investigated in detail in cultured HT22 neuronal cells, where the amino acid glutamate at high concentrations causes glutathione depletion by inhibition of the glutamate/cystine antiporter system, intracellular accumulation of reactive oxygen species (ROS) and eventually oxidative stress-induced neuronal cell death. Using this paradigm, we have previously reported that resveratrol (3,5,4'-trans-trihydroxystilbene) protects HT22 neuronal cells from glutamate-induced oxidative stress by inducing heme oxygenase (HO)-1 expression. Piceatannol (3,5,4',3'-trans-trihydroxystilbene), which is a hydroxylated resveratrol analog and one of the resveratrol metabolites, is estimated to exert neuroprotective effect similar to that of resveratrol. The aim of this study, thus, is to determine whether piceatannol, similarly to resveratrol, would protect HT22 neuronal cells from glutamate-induced oxidative stress. Glutamate at high concentrations induced neuronal cell death and ROS formation. Piceatannol reduced glutamate-induced cell death and ROS formation. The observed cytoprotective effect was much higher when HT22 neuronal cells were pretreated with piceatannol for 6 or 12 h prior to glutamate treatment than when pretreated for 0.5 h. Piceatannol also increased HO-1 expression and HO activity via its activation of nuclear factor-E2-related factor 2 (Nrf2). Interestingly, neuroprotective effect of piceatannol was partly (but not completely) abolished by either down-regulation of HO-1 expression or blockage of HO-1 activity. Taken together, our results suggest that piceatannol, similar to resveratrol, is capable of protecting HT22 neuronal cells against glutamate-induced cell death, at least in part, by inducing Nrf2-dependent HO-1 expression.
氧化应激引起的神经元细胞死亡在多种神经疾病中很常见，可以在培养的 HT22 神经元细胞中详细研究，其中高浓度的氨基酸谷氨酸通过抑制谷氨酸/胱氨酸反向转运系统导致谷胱甘肽耗竭，细胞内活性氧（ROS）的积累，最终导致氧化应激诱导的神经元细胞死亡。使用这种范式，我们之前报道过白藜芦醇（3,5,4'-反式三羟基二苯乙烯）通过诱导血红素加氧酶（HO）-1 的表达来保护 HT22 神经元细胞免受谷氨酸诱导的氧化应激。白藜芦醇的羟基化类似物之一、白藜芦醇的一种代谢物之一的白皮杉醇（3,5,4',3'-反式三羟基二苯乙烯）估计具有类似于白藜芦醇的神经保护作用。因此，本研究的目的是确定白皮杉醇是否与白藜芦醇类似，可保护 HT22 神经元细胞免受谷氨酸诱导的氧化应激。高浓度的谷氨酸诱导神经元细胞死亡和 ROS 形成。白皮杉醇减少了谷氨酸诱导的细胞死亡和 ROS 的形成。与在谷氨酸处理前仅预处理 0.5 小时相比，当 HT22 神经元细胞在谷氨酸处理前预处理 6 或 12 小时时，观察到的细胞保护作用要高得多。白皮杉醇还通过激活核因子-E2 相关因子 2（Nrf2）增加 HO-1 表达和 HO 活性。有趣的是，通过下调 HO-1 表达或阻断 HO-1 活性，白皮杉醇的神经保护作用部分（但不完全）被消除。综上所述，我们的结果表明，白皮杉醇与白藜芦醇类似，能够通过诱导 Nrf2 依赖性 HO-1 表达，至少部分地保护 HT22 神经元细胞免受谷氨酸诱导的细胞死亡。
