title: Targeting of microRNA-199a-5p protects against pilocarpine-induced status epilepticus and seizure damage via SIRT1-p53 cascade.
abstract: MicroRNAs (miRNAs) are noncoding small RNAs that control gene expression at the posttranscriptional level. Some dysregulated miRNAs have been shown to play important roles in epileptogenesis. The aim of this study was to determine if miR-199a-5p regulates seizures and seizure damage by targeting the antiapoptotic protein silent information regulator 1 (SIRT1).
  
  
  
  Hippocampal expression levels of miR-199a-5p, SIRT1, and acetylated p53 were quantified by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting in the acute, latent, and chronic stages of epilepsy in a rat lithium-pilocarpine epilepsy model. Silencing of miR-199a-5p expression in vivo was achieved by intracerebroventricular injection of antagomirs. The effects of targeting miR-199a-5p and SIRT1 protein on seizure and epileptic damage post-status epilepticus were assessed by electroencephalography (EEG) and immunohistochemistry, respectively.
  
  
  
  miR-199a-5p expression was up-regulated, SIRT1 levels were decreased, and neuron loss and apoptosis were induced in epilepsy model rats compared with normal controls, as determined by up-regulation of acetylated p53 and cleaved caspase-3 expression. In vivo knockdown of miR-199a-5p by an antagomir alleviated the seizure-like EEG findings and protected against neuron damage, in accordance with up-regulation of SIRT1 and subsequent deacetylation of p53. Furthermore, the seizure-suppressing effect of the antagomir was partly SIRT1 dependent.
  
  
  
  The results of this study suggest that silencing of miR-199a-5p exerts a seizure-suppressing effect in rats, and that SIRT1 is a direct target of miR-199a-5p in the hippocampus. The effect of miR-199a-5p on seizures and seizure damage is mediated via down-regulation of SIRT1. The miR-199a-5p/SIRT1 pathway may thus represent a potential target for the prevention and treatment of epilepsy and epileptic damage.
authors.affiliation: Department of Neurosurgery, Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Zhenlu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Minghai
authors.initials: M
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Neurosurgery, Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Ningwei
authors.initials: N
authors.lastname: Che
authors.affiliation: Department of Neurosurgery, Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Neurosurgery, Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yin
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D060565:Argonaute Proteins / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018021:Lithium Chloride / Q000633:toxicity; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D056564:Sirtuin 1 / Q000378:metabolism*; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D000927:Anticonvulsants; D060565:Argonaute Proteins; D002227:Carbazoles; D003292:Convulsants; C552425:MIRN199 microRNA, rat; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D016159:Tumor Suppressor Protein p53; D010862:Pilocarpine; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D018021:Lithium Chloride
keywords: Apoptosis; Epilepsy; Hippocampus neuron; SIRT1; miRNA-199a