Luo Lidan, Kim Seung-Woo, Lee Hye-Kyung, Kim Il-Doo, Lee Hahnbie, Lee Ja-Kyeong
Department of Anatomy, Inha University School of Medicine, Inchon, Korea.
Medical Research Center, Inha University School of Medicine, Inchon, Korea.
PLoS One. 2017 May 10;12(5):e0177322. doi: 10.1371/journal.pone.0177322. eCollection 2017.
4-Hydroxybenzyl alcohol (4-HBA) is an important phenolic constituent of Gastrodia elata Blume (GEB), a traditional herbal medicine used in East Asia. Many activities have been reported to underlie the beneficial effects of 4-HBA in the brain, and in particular, its anti-inflammatory, anti-oxidative, and anti-zinc-toxic effects have been implicated in the postischemic brain. Here, the authors investigated the anti-oxidative effect of 4-HBA on astrocytes and sought to identify the underlying molecular mechanisms involved. 4-HBA dose-dependently suppressed H2O2-induced astrocyte cell death. More specifically, pre-incubation of C6 cells (an astrocyte cell line) with 100 μM 4-HBA for 6 hrs increased survival when cells were treated with H2O2 (100 μM, 1 hr) from 54.2±0.7% to 85.9±1.5%. In addition, 4-HBA was found to up-regulate and activate Nrf2, and subsequently, to induce the expressions of several anti-oxidative genes, such as, HO-1, NQO1, and GCLM. Notably, HO-1 was induced by 3.4-fold in 4-HBA-treated C6 cells, and siRNA-mediated HO-1 knockdown demonstrated that Nrf2 activation and HO-1 induction were responsible for the observed cytoprotective effect of 4-HBA. ERK and Akt signaling pathways were activated by 4-HBA in C6 cells, suggesting their involvements in protective effect of 4-HBA. In addition, 4-HBA-conditioned astrocyte culture medium was found to have neuroprotective effects on primary neuronal cultures or fresh C6 cells exposed to oxidative stress, and these effects seemed to be mediated by glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), which both accumulated in 4-HBA-treated astrocyte culture media. Thus, the 4-HBA-mediated activation of Nrf2 and induction of HO-1 in astrocytes were found to act via autocrine and paracrine mechanisms to confer protective effects. Furthermore, given the pleiotropic effects of 4-HBA with respect to its targeting of various brain cell types and functions, it would appear that 4-HBA has therapeutic potential for the prevention and amelioration of various brain diseases.
4-羟基苯甲醇（4-HBA）是天麻（GEB）的一种重要酚类成分，天麻是东亚地区使用的一种传统草药。据报道，4-HBA在大脑中的有益作用有多种机制，特别是其抗炎、抗氧化和抗锌毒性作用与缺血后脑有关。在此，作者研究了4-HBA对星形胶质细胞的抗氧化作用，并试图确定其潜在的分子机制。4-HBA剂量依赖性地抑制H2O2诱导的星形胶质细胞死亡。更具体地说，用100μM 4-HBA预孵育C6细胞（一种星形胶质细胞系）6小时，当细胞用H2O2（100μM，1小时）处理时，细胞存活率从54.2±0.7%提高到85.9±1.5%。此外，发现4-HBA上调并激活Nrf2，随后诱导几种抗氧化基因的表达，如HO-1、NQO1和GCLM。值得注意的是，在4-HBA处理的C6细胞中，HO-1的诱导倍数为3.4倍，siRNA介导的HO-1敲低表明Nrf2激活和HO-1诱导是4-HBA观察到的细胞保护作用的原因。ERK和Akt信号通路在C6细胞中被4-HBA激活，表明它们参与了4-HBA的保护作用。此外，发现4-HBA条件培养的星形胶质细胞培养基对暴露于氧化应激的原代神经元培养物或新鲜C6细胞具有神经保护作用，这些作用似乎是由胶质细胞源性神经营养因子（GDNF）和血管内皮生长因子（VEGF）介导的，它们都在4-HBA处理的星形胶质细胞培养基中积累。因此，发现4-HBA介导的星形胶质细胞中Nrf2的激活和HO-1的诱导通过自分泌和旁分泌机制发挥保护作用。此外，鉴于4-HBA对各种脑细胞类型和功能的多效性作用，4-HBA似乎具有预防和改善各种脑部疾病的治疗潜力。
