Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, Japan.
J Neurochem. 2012 Jan;120(2):279-91. doi: 10.1111/j.1471-4159.2011.07570.x. Epub 2011 Nov 24.
Paraquat is a widely used herbicide that is structurally similar to the known dopaminergic neurotoxicant 1-methyl-4-phenyl-pyridine and acts as a potential etiologic factor for the development of Parkinson's disease. In this study, we investigated the protective roles of lipocalin-type prostaglandin (PG) D synthase (L-PGDS) against paraquat-mediated apoptosis of human neuronal SH-SY5Y cells. The treatment of SH-SY5Y cells with paraquat decreased the intracellular GSH level, and enhanced the cell death with elevation of the caspase activities. L-PGDS was expressed in SH-SY5Y cells, and its expression was enhanced with the peak at 2 h after the initiation of the treatment with paraquat. Inhibition of PGD₂ synthesis and exogenously added PGs showed no effects regarding the paraquat-mediated apoptosis. SiRNA-mediated suppression of L-PGDS expression in the paraquat-treated cells increased the cell death and caspase activities. Moreover, over-expression of L-PGDS suppressed the cell death and caspase activities in the paraquat-treated cells. The results of a promoter-luciferase assay demonstrated that paraquat-mediated elevation of L-PGDS gene expression occurred through the NF-κB element in the proximal promoter region of the L-PGDS gene in SH-SY5Y cells. These results indicate that L-PGDS protected against the apoptosis in the paraquat-treated SH-SY5Y cells through the up-regulation of L-PGDS expression via the NF-κB element. Thus, L-PGDS might potentially serve as an agent for prevention of human neurodegenerative diseases caused by oxidative stress and apoptosis.
百草枯是一种广泛使用的除草剂，其结构与已知的多巴胺能神经毒性 1-甲基-4-苯基-吡啶相似，是帕金森病发展的潜在病因。在这项研究中，我们研究了脂联素型前列腺素（PG）D 合酶（L-PGDS）对百草枯介导的人神经元 SH-SY5Y 细胞凋亡的保护作用。百草枯处理 SH-SY5Y 细胞会降低细胞内 GSH 水平，并通过提高半胱天冬酶活性增强细胞死亡。SH-SY5Y 细胞中表达 L-PGDS，其表达在百草枯处理后 2 小时达到峰值。抑制 PGD₂合成和外源性添加 PGs 对百草枯介导的凋亡没有影响。百草枯处理细胞中 L-PGDS 的 siRNA 抑制增加了细胞死亡和半胱天冬酶活性。此外，过表达 L-PGDS 抑制了百草枯处理细胞中的细胞死亡和半胱天冬酶活性。启动子-荧光素酶测定的结果表明，百草枯通过 NF-κB 元件介导 SH-SY5Y 细胞中 L-PGDS 基因表达的上调。这些结果表明，L-PGDS 通过 NF-κB 元件上调 L-PGDS 表达来保护百草枯处理的 SH-SY5Y 细胞免受凋亡。因此，L-PGDS 可能通过预防氧化应激和凋亡引起的人类神经退行性疾病而具有潜在的用途。
