title: MicroRNA-139-5p negatively regulates NR2A-containing NMDA receptor in the rat pilocarpine model and patients with temporal lobe epilepsy.
abstract: Regulation of N-methyl-d-aspartate (NMDA) subunits NR2A and NR2B expression during status epilepticus (SE) remains incompletely understood. Here we explored the role of brain-enriched microRNA (miR)-139-5p in this process.
  
  
  
  miRNA microarray was performed to examine changes in miRNA expression in the rat pilocarpine model following NMDA-receptor blockade. The dynamic expression patterns of miR-139-5p, NR2A, and NR2B levels were measured in rats during the three phases of temporal lobe epilepsy (TLE) development using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. Similar expression methods were applied to hippocampi obtained from patients with TLE and from normal controls. Moreover, miR-139-5p agomir and antagomir were utilized to explore the role of miR-139-5p in determining NMDA-receptor subunit expression patterns.
  
  
  
  We identified 18 miRNAs that were significantly altered in the rat pilocarpine model following NMDA-receptor blockade. Of these, miR-139-5p was significantly up-regulated and Grin2A was predicted as its potential putative target. In patients with TLE, miR-139-5p expression was significantly down-regulated, whereas NR2A and NR2B levels were significantly up-regulated. In the rat model of SE, miR-139-5p expression was down-regulated while NR2A was up-regulated in the acute and chronic phases, but not in the latent phase. NR2B expression was up-regulated during the three phases of TLE development. Overexpression of miR-139-5p decreased, whereas depletion of miR-139-5p enhanced the expression levels of NR2A, but not NR2B, induced by pilocarpine treatment. Of interest, NMDA nonselective antagonist and NR2A selective antagonist enhanced miR-139-5p levels suppressed by pilocarpine treatment, whereas the NR2B selective antagonist was ineffective.
  
  
  
  These findings elucidate the potential role of miR-139-5p in NMDA-receptor involvement in TLE development and may provide novel therapeutic targets for the future treatment of TLE.
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Walid A
authors.initials: WA
authors.lastname: Alsharafi
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000473:pathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D063990:Gene Ontology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018721:Muscarinic Agonists / Q000633:toxicity; D020411:Oligonucleotide Array Sequence Analysis; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: D018691:Excitatory Amino Acid Antagonists; C000600035:MIRN139 microRNA, rat; D035683:MicroRNAs; D018721:Muscarinic Agonists; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D010862:Pilocarpine; D016291:Dizocilpine Maleate
keywords: Hippocampus; MicroRNAs; N-methyl-d-aspartate; NR2A-containing NMDA receptor; Temporal lobe epilepsy