Abstract
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.
Highlights
Drug abuse and addiction are devastating health conditions in modern society
We examined the impact of cocaine on the mRNA expression of methylation regulators (DNMTs) in astrocytes
We found that cocaine treatment downregulated the mRNA expression of DNA methyltransferases (DNMTs)-1 and DNMT-3A and upregulated the expression of DNMT-3B
Summary
Drug abuse and addiction are devastating health conditions in modern society. In the UnitedStates, an estimated 8.5 million people suffer from a mental health disorder, a substance use disorder or both [1,2]. The diverse actions of psychostimulants affect intracellular signalling and can alter cellular function, which leads to the behavioural and psychological abnormalities underlying addiction syndrome [3]. These long-lasting neuroadaptations are involved in stable epigenetic modifications to DNA in the central nervous system (CNS), which influences gene regulation through DNA methylation and posttranslational modification, including methylation, phosphorylation, acetylation and deacetylation, of histone proteins [4,5,6]. DNA methylation and its role in gene transcription silencing, of which DNA methyltransferases (DNMTs) are important regulators, have been the main focus of epigenetic studies [7]. All three DNMTs are required for methylation maintenance and embryonic development [10,11]
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