Protective Role for the Disulfide Isomerase PDIA3 in Methamphetamine Neurotoxicity. Macaca mulatta

Methamphetamine abuse continues to be a worldwide problem, damaging the individual user as well as society. Only minimal information exists on molecular changes in the brain that result from methamphetamine administered in patterns typical of human abusers. In order to investigate such changes, we examined the effect of methamphetamine on the transcriptional profile in brains of monkeys. Gene expression profiling of the caudate and hippocampus identified protein disulfide isomerase family member A3 (PDIA3) to be significantly up-regulated in the animals treated with methamphetamine as compared to saline treated control monkeys. Treatment of primary rat neurons with methamphetamine revealed an up-regulation of PDIA3, showing a direct effect of methamphetamine on neurons to increase PDIA3. In vitro studies using a neuroblastoma cell line demonstrated that PDIA3 expression protects against methamphetamine-induced cell toxicity and methamphetamine-induced intracellular reactive oxygen species production, revealing a neuroprotective role for PDIA3. The current study implicates PDIA3 to be an important cellular neuroprotective mechanism against a toxic drug, and as a potential target for therapeutic investigations. Overall design: To study the effects of chronic METH effects on the brain

甲基苯丙胺（Methamphetamine）滥用至今仍是全球性公共卫生难题，不仅损害使用者个体健康，亦对社会造成严重危害。目前针对人类滥用者典型给药模式下甲基苯丙胺所致脑部分子改变的相关研究资料仍十分有限。为探究此类改变，本研究以猴为实验模型，考察甲基苯丙胺对其脑部转录组谱（transcriptional profile）的影响。对尾状核（caudate）与海马体（hippocampus）的基因表达谱分析显示，相较于生理盐水处理的对照猴，甲基苯丙胺处理组猴脑内的蛋白质二硫键异构酶家族成员A3（PDIA3）表达显著上调。采用甲基苯丙胺处理原代大鼠神经元的实验结果显示，PDIA3表达同样出现上调，表明甲基苯丙胺可直接作用于神经元以提升PDIA3的表达水平。通过神经母细胞瘤细胞系开展的体外实验证实，PDIA3的表达可抵御甲基苯丙胺诱导的细胞毒性及细胞内活性氧（reactive oxygen species）生成，由此揭示了PDIA3的神经保护作用。本研究表明，PDIA3是对抗该毒性药物的重要细胞神经保护机制，同时也可作为相关治疗研究的潜在靶点。整体实验设计：探究慢性甲基苯丙胺暴露对脑部的影响。