Abstract
BackgroundA 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 FindingsCXCR4 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.ConclusionsOur 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.
Highlights
Primary open-angle glaucoma (POAG), one of the leading causes of irreversible visual impairment worldwide [1], is characterized as a multi-factorial optic neuropathy [2,3,4]
Our findings demonstrate that CXCR4 might be involved in the pathogenetic changes in the trabecular meshwork of patients with POAG
TMP might exert its beneficial effects in POAG patients by down-regulating CXCR4 expression
Summary
Primary open-angle glaucoma (POAG), one of the leading causes of irreversible visual impairment worldwide [1], is characterized as a multi-factorial optic neuropathy [2,3,4]. Pathological ocular hypertension is the principle factor involved in the progression of optic neuropathy in POAG [5] It is commonly initiated by impaired outflow of the aqueous humor and results from trabecular meshwork (TM) abnormalities, which include extracellular matrix (ECM) accumulation and structural changes in the actin cytoskeleton [6]. 2,3,5,6-Tetramethylpyrazine (TMP), the bioactive component of Chuanxiong, has been prescribed in the clinic as a complementary treatment for glaucoma to improve patient prognosis. Previous studies have reported that Chuanxiong therapy has a remarkable ability to control IOP in glaucoma patients, including via acupuncture injection, as a complementary treatment after surgery and in combination with other Chinese herbal medicines [8,9,10]. We further investigated whether the SDF-1/CXCR4 pathway is involved in the TMP-mediated activity in trabecular meshwork cells
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