Choi Mi Ran, Chun Ji-Won, Kwak Su Min, Bang Sol Hee, Jin Yeung-Bae, Lee Youngjeon, Kim Han-Na, Chang Kyu-Tae, Chai Young Gyu, Lee Sang-Rae, Kim Dai-Jin
Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Republic of Korea.
National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, Republic of Korea.
Toxicol Appl Pharmacol. 2018 Sep 15;355:68-79. doi: 10.1016/j.taap.2018.05.031. Epub 2018 May 23.
Methamphetamine (MA), a psychostimulant abused worldwide, gives rise to neurotoxicity in the hippocampus, resulting in cognitive impairments and hippocampal volume reduction. The cellular and molecular mechanisms associated with hippocampal impairments due to MA remain unknown. The aim of this study was to investigate the effects of MA on structural alterations and gene expressions in the hippocampus. We analyzed the pattern of volumetric changes in the hippocampus using magnetic resonance imaging (MRI) after acute and chronic administration of MA to cynomolgus macaques. In addition, we performed large-scale transcriptome profiling in the hippocampus using RNA-Seq technology. The hippocampus in response to acute and chronic MA exhibited a significant volumetric atrophy compared with the hippocampus of controls. The genes associated with cytoskeleton organization and phagocytosis were downregulated in the acute MA-treated group compared to the control group. On the other hand, genes associated with synaptic transmission, regulation of neuron differentiation and regulation of neurogenesis were downregulated in the chronic MA-treated group. We confirmed that expression patterns for ADM, BMP4, CHRD, PDYN, UBA1, profilin 2 (PFN2), ENO2 and NSE mRNAs were similar to the results from RNA-Seq based on quantitative RT-PCR. In particular, PFN2 mRNA and protein expression levels, which play important roles in actin cytoskeleton dynamics, were decreased by acute and chronic MA administration. These results not only aid the understanding of cellular and molecular mechanisms regulated by MA in the hippocampus but also suggest basic information aiding biomarker and novel drug development for treating hippocampal impairment caused by MA abuse.
甲基苯丙胺（MA）是一种在全球范围内被滥用的精神兴奋剂，会导致海马体神经毒性，进而造成认知障碍和海马体体积减小。与MA导致的海马体损伤相关的细胞和分子机制尚不清楚。本研究的目的是调查MA对海马体结构改变和基因表达的影响。我们在食蟹猕猴急性和慢性给予MA后，使用磁共振成像（MRI）分析了海马体体积变化模式。此外，我们使用RNA测序技术对海马体进行了大规模转录组分析。与对照组的海马体相比，急性和慢性MA处理后的海马体均出现了明显的体积萎缩。与对照组相比，急性MA处理组中与细胞骨架组织和吞噬作用相关的基因下调。另一方面，慢性MA处理组中与突触传递、神经元分化调节和神经发生调节相关的基因下调。我们证实，基于定量逆转录聚合酶链反应（RT-PCR），ADM、BMP4、CHRD、PDYN、UBA1、丝切蛋白2（PFN2）、烯醇化酶2（ENO2）和神经元特异性烯醇化酶（NSE）mRNA的表达模式与RNA测序结果相似。特别是，在肌动蛋白细胞骨架动力学中起重要作用的PFN2 mRNA和蛋白表达水平，在急性和慢性给予MA后均降低。这些结果不仅有助于理解MA在海马体中调节的细胞和分子机制，还为治疗MA滥用引起的海马体损伤的生物标志物和新型药物开发提供了基础信息。
