Reactive oxygen species production and MAPK activation are implicated in tetrahydrobiopterin-induced SH-SY5Y cell death
Reactive oxygen species production and MAPK activation are implicated in tetrahydrobiopterin-induced SH-SY5Y cell death
复制标题
DOI：
10.1016/j.neulet.2008.10.106
复制
发表时间：
2009-01-16
影响因子：
2.5
通讯作者：
Chongthammakun, Sukumal
中科院分区：
文献类型：
--
作者：
Chongthammakun, Vasutakarn;Sanvarinda, Yupin;Chongthammakun, Sukumal
四氢生物蝶呤（Tetrahydrobiopterin，BH 4）是多巴胺（dopamine，DA）合成的一种辅助因子，在帕金森病（Parkinson's disease，PD）的体内和体外模型中，BH 4自氧化产生活性氧（reactive oxygen species，ROS），诱导选择性多巴胺能细胞死亡。然而，BH 4暴露后神经元死亡的确切分子机制尚未得到很好的阐明。本研究的目的是研究细胞内活性氧的产生和信号转导途径的潜在的BH 4对人多巴胺能SH-SY 5 Y细胞的毒性作用。结果表明，BH 4处理浓度范围从50 W至400 μ M诱导神经元死亡的剂量依赖性方式。伴随着细胞内ROS形成的升高，通过用MAPK抑制剂SB 203580或PD 98059预处理，BH 4诱导的SH-SY 5 Y细胞中MAPK、p38和ERK 1/2的活化被减弱。这些数据表明，MAPK激活和氧化应激参与BH 4诱导的多巴胺能细胞死亡，可能通过BH 4的自氧化和随后的ROS产生。(c)2008爱思唯尔爱尔兰有限公司保留所有权利。
Tetrahydrobiopterin (BH4), an obligatory cofactor for dopamine (DA) synthesis, has been shown to produce reactive oxygen species (ROS) upon its autoxidation and induce selective dopaminergic cell death in many in vivo and in vitro models of Parkinson's disease (PD). The precise molecular mechanisms underlying neuronal death upon BH4 exposure, however, have not yet been well elucidated. The present study aims to examine the intracellular ROS production and the signal transduction pathways underlying the toxic effects of BH4 on human dopaminergic SH-SY5Y cells. The results show that BH4 treatment at concentrations ranging from 50 W to 400 mu M induces neuronal death in a dose-dependent manner. In concomitant with the elevation of intracellular ROS formation, BH4-induced activation of MAPK, p38 and ERK1/2 in SH-SY5Y cells is attenuated by pretreatment with MAPK inhibitors, SB203580 or PD98059. These data indicate that MAPK activation and oxidative stress are involved in BH4-induced dopaminergic cell death, possibly through the autoxidation of BH4 and subsequent ROS production. (c) 2008 Elsevier Ireland Ltd. All rights reserved.