Omonijo Oluwaseyi, Wongprayoon Pawaris, Ladenheim Bruce, McCoy Michael T, Govitrapong Piyarat, Jayanthi Subramaniam, Cadet Jean Lud
Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD 21224, United States.
Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Thailand.
Neurotoxicology. 2014 Dec;45:178-84. doi: 10.1016/j.neuro.2014.10.008. Epub 2014 Oct 27.
Methamphetamine use disorder is characterized by recurrent binge episodes. Humans addicted to methamphetamine experience various degrees of cognitive deficits and show evidence of neurodegenerative processes in the brain. Binge injections of METH to rodents also cause significant toxic changes in the brain. In addition, this pattern of METH injections can alter gene expression in the dorsal striatum. Gene expression is regulated, in part, by histone deacetylation. We thus tested the possibility that METH toxic doses might cause changes in the mRNA levels of histone deacetylases (HDACs). We found that METH did produce significant decreases in the mRNA expression of HDAC8, which is a class I HDAC. METH also decreased expression of HDAC6, HDAC9, and HDAC10 that are class II HDACs. The expression of the class IV HDAC, HDAC11, was also suppressed by METH. The expression of Sirt2, Sirt5, and Sirt6 that are members of class III HDACs was also downregulated by METH injections. Our findings implicate changes in HDAC expression may be an early indicator of impending METH-induced neurotoxicity in the striatum. This idea is consistent with the accumulated evidence that some HDACs are involved in neurodegenerative processes in the brain.
甲基苯丙胺使用障碍的特征是反复出现暴饮暴食发作。对甲基苯丙胺成瘾的人会经历不同程度的认知缺陷，并显示出大脑神经退行性变过程的证据。对啮齿动物进行甲基苯丙胺的暴饮暴食注射也会导致大脑发生显著的毒性变化。此外，这种甲基苯丙胺注射模式可以改变背侧纹状体中的基因表达。基因表达部分受组蛋白去乙酰化调节。因此，我们测试了甲基苯丙胺毒性剂量可能导致组蛋白去乙酰化酶（HDACs）mRNA水平变化的可能性。我们发现甲基苯丙胺确实使I类HDAC即HDAC8的mRNA表达显著降低。甲基苯丙胺还降低了II类HDAC即HDAC6、HDAC9和HDAC10的表达。IV类HDAC即HDAC11的表达也被甲基苯丙胺抑制。III类HDAC成员即Sirt2、Sirt5和Sirt6的表达也因甲基苯丙胺注射而下调。我们的研究结果表明，HDAC表达的变化可能是甲基苯丙胺诱导的纹状体神经毒性即将发生的早期指标。这一观点与一些HDAC参与大脑神经退行性变过程的累积证据一致。
