Tetramethylpyrazine (TMP), an Active Ingredient of Chinese Herb Medicine Chuanxiong, Attenuates the Degeneration of Trabecular Meshwork through SDF-1/CXCR4 Axis.
Tetramethylpyrazine (TMP), an Active Ingredient of Chinese Herb Medicine Chuanxiong, Attenuates the Degeneration of Trabecular Meshwork through SDF-1/CXCR4 Axis.
复制标题
中药川芎的活性成分四甲基吡嗪 (TMP) 通过 SDF-1/CXCR4 轴减轻小梁网变性
DOI：
10.1371/journal.pone.0133055
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Zhuang J
中科院分区：
文献类型：
--
作者：
Yu N;Zhang Z;Chen P;Zhong Y;Cai X;Hu H;Yang Y;Zhang J;Li K;Ge J;Yu K;Liu X;Zhuang J
背景中药川芎嗪（Tetramethylpyrazine， TMP）已被作为青光眼的辅助治疗，以改善患者预后。然而，TMP的药理作用机制尚不清楚。在之前的研究中，我们发现TMP对新生血管有强大的抑制作用，抑制胶质瘤细胞的致瘤行为，并通过调节CXCR4的表达来保护神经细胞。在这里，我们进一步研究了SDF-1/CXCR4通路是否也参与了小梁网细胞中tmp介导的活性。采用实时荧光定量PCR检测54例原发性开角型青光眼（POAG）手术患者和19例非青光眼供体的小梁和虹膜标本中CXCR4的表达。我们的数据显示，与对照组相比，POAG患者小梁网中CXCR4的表达明显升高。与此一致的是，CXCR4在青光眼小梁网细胞中的表达远高于正常小梁网细胞。通过RT-PCR和western blot检测，我们发现青光眼相关细胞因子和地塞米松（DEX）也显著上调了原代人小梁网（PHTM）细胞中CXCR4的表达。此外，与对照处理（PBS）和CXCR4拮抗剂AMD3100相比，TMP显著下调TGF-β1介导的PHTM细胞中CXCR4表达。此外，TMP可以抵消TGF-β1诱导的PHTM细胞应激纤维积累和扩张的影响。在transwell和抓伤实验中，TMP明显抑制TGF-β1刺激的PHTM细胞的迁移。TMP还能抑制TGF-β2诱导的细胞外基质（ECM）积累。结论CXCR4可能参与了POAG患者小梁网的病理改变。此外，TMP可能通过下调CXCR4的表达而在POAG患者中发挥有益作用。
Background A traditional Chinese medicine, Tetramethylpyrazine (TMP), has been prescribed as a complementary treatment for glaucoma to improve patient prognosis. However, the pharmacological mechanism of action of TMP is poorly understood. In previous studies, we demonstrated that TMP exerts potent inhibitory effects on neovascularization, suppresses the tumorigenic behavior of glioma cells, and protects neural cells by regulating CXCR4 expression. Here, we further investigated whether the SDF-1/CXCR4 pathway is also involved in the TMP-mediated activity in trabecular meshwork cells. Methodology/Principal Findings CXCR4 expression was examined by quantitative real-time PCR in trabecular and iris specimens from 54 primary open-angle glaucoma (POAG) patients who required surgery and 19 non-glaucomatous donors. Our data revealed markedly elevated CXCR4 expression in the trabecular meshwork of POAG patients compared with that of controls. Consistently, CXCR4 expression was much higher in glaucomatous trabecular meshwork cells than in normal trabecular meshwork cells. Using RT-PCR and western blot assays, we determined that glaucoma-related cytokines and dexamethasone (DEX) also significantly up-regulated CXCR4 expression in primary human trabecular meshwork (PHTM) cells. Moreover, the TGF-β1-mediated induction of CXCR4 expression in PHTM cells was markedly down-regulated by TMP compared with control treatment (PBS) and the CXCR4 antagonist AMD3100. In addition, TMP could counteract the TGF-β1-induced effects on stress fiber accumulation and expansion of PHTM cells. TMP markedly suppressed the migration of PHTM cells stimulated by TGF-β1 in transwell and scratch wound assays. TMP also suppressed the extracellular matrix (ECM) accumulation induced by TGF-β2. Conclusions Our findings demonstrate that CXCR4 might be involved in the pathogenetic changes in the trabecular meshwork of patients with POAG. Additionally, TMP might exert its beneficial effects in POAG patients by down-regulating CXCR4 expression.