title: Cocaine-mediated downregulation of microglial miR-124 expression involves promoter DNA methylation.
abstract: Neuroinflammation plays a critical role in the development of reward-related behavior in cocaine self-administration rodents. Cocaine, one of most commonly abused drugs, has been shown to activate microglia both in vitro and in vivo. Detailed molecular mechanisms underlying cocaine-mediated microglial activation remain poorly understood. microRNAs (miRs) belonging to a class of small noncoding RNA superfamily have been shown to modulate the activation status of microglia. miR-124, one of the microglia-enriched miRs, functions as an anti-inflammatory regulator that maintains microglia in a quiescent state. To date, the possible effects of cocaine on microglial miR-124 levels and the associated underlying mechanisms have not been explored. In the current study, we demonstrated that cocaine exposure decreased miR-124 levels in both BV-2 cells and rat primary microglia. These findings were further validated in vivo, wherein we demonstrated decreased abundance of miR-124 in purified microglia isolated from cocaine-administered mice brains compared with cells from saline administered animals. Molecular mechanisms underlying these effects involved cocaine-mediated increased mRNA and protein expression of DNMTs in microglia. Consistently, cocaine substantially increased promoter DNA methylation levels of miR-124 precursors (pri-miR-124-1 and -2), but not that of pri-miR-124-3, both in vitro and in vivo. In summary, our findings demonstrated that cocaine exposure increased DNA methylation of miR-124 promoter resulting into its downregulation, which, in turn, led to microglial activation. Our results thus implicate that epigenetic modulation of miR-124 could be considered as a potential therapeutic approach to ameliorate microglial activation and, possibly, the development of cocaine addiction.
authors: a Department of Pharmacology and Experimental Neuroscience , Nebraska Medical Center, University of Nebraska Medical Center , Omaha , NE , USA.
authors: Ming-Lei
authors: ML
authors: Guo
authors: a Department of Pharmacology and Experimental Neuroscience , Nebraska Medical Center, University of Nebraska Medical Center , Omaha , NE , USA.
authors: Palsamy
authors: P
authors: Periyasamy
authors: a Department of Pharmacology and Experimental Neuroscience , Nebraska Medical Center, University of Nebraska Medical Center , Omaha , NE , USA.
authors: Ke
authors: K
authors: Liao
authors: a Department of Pharmacology and Experimental Neuroscience , Nebraska Medical Center, University of Nebraska Medical Center , Omaha , NE , USA.
authors: Yeon Hee
authors: YH
authors: Kook
authors: a Department of Pharmacology and Experimental Neuroscience , Nebraska Medical Center, University of Nebraska Medical Center , Omaha , NE , USA.
authors: Fang
authors: F
authors: Niu
authors: a Department of Pharmacology and Experimental Neuroscience , Nebraska Medical Center, University of Nebraska Medical Center , Omaha , NE , USA.
authors: Shannon E
authors: SE
authors: Callen
authors: a Department of Pharmacology and Experimental Neuroscience , Nebraska Medical Center, University of Nebraska Medical Center , Omaha , NE , USA.
authors: Shilpa
authors: S
authors: Buch
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003042:Cocaine / Q000378:metabolism / Q000633:toxicity*; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D017628:Microglia / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats
chemical_list: C548144:MIRN124 microRNA, rat; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D003042:Cocaine
keywords: Cocaine; miR-124; microglial cells; neuroinflammation; promoter DNA methylation