AC927, a σ Receptor Ligand, Blocks Methamphetamine-Induced Release of Dopamine and Generation of Reactive Oxygen Species in NG108-15 Cells
AC927, a σ Receptor Ligand, Blocks Methamphetamine-Induced Release of Dopamine and Generation of Reactive Oxygen Species in NG108-15 Cells
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DOI：
10.1124/mol.111.074120
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发表时间：
2012-03-01
影响因子：
3.6
通讯作者：
Matsumoto, Rae R.
中科院分区：
文献类型：
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作者：
Kaushal, Nidhi;Elliott, Meenal;Matsumoto, Rae R.
甲基苯丙胺是一种高度成瘾性的精神兴奋剂药物，滥用时高剂量或重复服用会引起神经毒性。早期的研究证明了选择性sigma受体配体n -苯乙基哌啶草酸酯（AC927）在体内减轻甲基苯丙胺的神经毒性作用的能力。然而，AC927传递其保护作用的确切机制仍有待确定。以分化的NG108-15细胞为模型系统，在AC927缺失和存在的情况下，研究了甲基苯丙胺对神经毒性终点和介质如凋亡、坏死、活性氧（ROS）和活性氮（RNS）的产生以及多巴胺释放的影响。甲基安非他命微摩尔浓度引起NG108-15细胞凋亡。在较高浓度的甲基苯丙胺下，观察到坏死细胞死亡。在较早的时间点，甲基苯丙胺引起ROS/RNS的产生，用致荧光底物5-（和6）-氯甲基-2',7'-二氯二氢荧光素二醋酸酯，乙酰酯检测，以浓度和时间依赖性的方式。n -乙酰半胱氨酸、过氧化氢酶和l - ng单甲基精氨酸柠檬酸盐抑制甲基苯丙胺诱导的ROS/ RNS荧光信号，提示过氧化氢和RNS的形成。暴露于甲基苯丙胺也刺激了从NG108-15细胞释放到培养基中的多巴胺。AC927可减弱甲基苯丙胺诱导的NG108-15细胞凋亡、坏死、ROS/RNS生成和多巴胺释放。综上所述，数据表明调节sigma受体可以减轻甲基安非他明诱导的细胞毒性、ROS/RNS的产生和培养细胞中多巴胺的释放。
Methamphetamine is a highly addictive psychostimulant drug of abuse that causes neurotoxicity with high or repeated dosing. Earlier studies demonstrated the ability of the selective sigma receptor ligand N-phenethylpiperidine oxalate (AC927) to attenuate the neurotoxic effects of methamphetamine in vivo. However, the precise mechanisms through which AC927 conveys its protective effects remain to be determined. With the use of differentiated NG108-15 cells as a model system, the effects of methamphetamine on neurotoxic endpoints and mediators such as apoptosis, necrosis, generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and dopamine release were examined in the absence and presence of AC927. Methamphetamine at physiologically relevant micromolar concentrations caused apoptosis in NG108-15 cells. At higher concentrations of methamphetamine, necrotic cell death was observed. At earlier time points, methamphetamine caused ROS/RNS generation, which was detected with the fluorigenic substrate 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescin diacetate, acetyl ester, in a concentration-and time-dependent manner. N-Acetylcysteine, catalase, and L-NGmonomethyl arginine citrate inhibited the ROS/ RNS fluorescence signal induced by methamphetamine, which suggests the formation of hydrogen peroxide and RNS. Exposure to methamphetamine also stimulated the release of dopamine from NG108-15 cells into the culture medium. AC927 attenuated methamphetamine-induced apoptosis, necrosis, ROS/RNS generation, and dopamine release in NG108-15 cells. Together, the data suggest that modulation of sigma receptors can mitigate methamphetamine-induced cytotoxicity, ROS/RNS generation, and dopamine release in cultured cells.