Sivalingam Kalaiselvi, Samikkannu Thangavel
Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, 1010 W Avenue B, Kingsville, TX 78363, USA.
Brain Sci. 2020 Sep 5;10(9):611. doi: 10.3390/brainsci10090611.
Cocaine abuse is known to alter mitochondrial biogenesis and induce epigenetic modification linked with neuronal dysfunction. Cocaine-induced epigenetic modification of DNA methylation and the mitochondrial genome may affect mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), as epigenetic DNA methylation is key to maintaining genomic integrity in the central nervous system (CNS). However, the impact of cocaine-mediated epigenetic changes in astrocytes has not yet been elucidated. In this study, we explored the neuroprotective effect of piracetam against cocaine-induced epigenetic changes in DNA methylation in astrocytes. To study our hypothesis, we exposed human astrocytes to cocaine alone or in combination with the nootropic drug piracetam. We examined the expression of the DNA methyltransferases (DNMTs) DNMT-1, DNMT-3A, and DNMT-3B; global DNA methylation levels of 5-methycytosine (5-mC); and induction of ten-eleven translocation (TET) enzymes in astrocytes. In addition, we analyzed mtDNA methylation by targeted next-generation bisulfite sequencing. Our data provide evidence that cocaine impairs DNMT activity and thereby has impacts on mtDNA, which might contribute to the neurodegeneration observed in cocaine users. These effects might be at least partially prevented by piracetam, allowing neuronal function to be maintained.
众所周知，可卡因滥用会改变线粒体生物合成，并诱导与神经元功能障碍相关的表观遗传修饰。可卡因诱导的DNA甲基化和线粒体基因组的表观遗传修饰可能会影响线粒体DNA（mtDNA）和核DNA（nDNA），因为表观遗传DNA甲基化是维持中枢神经系统（CNS）基因组完整性的关键。然而，可卡因介导的星形胶质细胞表观遗传变化的影响尚未阐明。在本研究中，我们探讨了吡拉西坦对可卡因诱导的星形胶质细胞DNA甲基化表观遗传变化的神经保护作用。为了验证我们的假设，我们将人类星形胶质细胞单独暴露于可卡因或与益智药吡拉西坦联合暴露。我们检测了DNA甲基转移酶（DNMTs）DNMT-1、DNMT-3A和DNMT-3B的表达；5-甲基胞嘧啶（5-mC）的整体DNA甲基化水平；以及星形胶质细胞中十-十一易位（TET）酶的诱导情况。此外，我们通过靶向新一代亚硫酸氢盐测序分析了mtDNA甲基化。我们的数据提供了证据，表明可卡因会损害DNMT活性，从而对mtDNA产生影响，这可能导致可卡因使用者中观察到的神经退行性变。吡拉西坦可能至少部分预防这些影响，从而维持神经元功能。
