Targeting of micro RNA ‐199a‐5p protects against pilocarpine‐induced status epilepticus and seizure damage via SIRT 1‐p53 cascade

• Published in: Epilepsia (Copenhagen) Vol. 57; no. 5; pp. 706 - 716
• Main Authors: Wang, Dong, Li, Zhenlu, Zhang, Yukun, Wang, Guangzhi, Wei, Minghai, Hu, Yan, Ma, Shuo, Jiang, Yue, Che, Ningwei, Wang, Xiaofeng, Yao, Jihong, Yin, Jian
• Format: Journal Article
• Language: English
• Published: 01.05.2016
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.13348

Summary Objective Micro RNA s (mi RNA s) are noncoding small RNA s that control gene expression at the posttranscriptional level. Some dysregulated mi RNA s 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 ( SIRT 1). Methods Hippocampal expression levels of miR‐199a‐5p, SIRT 1, 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 SIRT 1 protein on seizure and epileptic damage post‐status epilepticus were assessed by electroencephalography ( EEG ) and immunohistochemistry, respectively. Results miR‐199a‐5p expression was up‐regulated, SIRT 1 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 SIRT 1 and subsequent deacetylation of p53. Furthermore, the seizure‐suppressing effect of the antagomir was partly SIRT 1 dependent. Significance The results of this study suggest that silencing of miR‐199a‐5p exerts a seizure‐suppressing effect in rats, and that SIRT 1 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 SIRT 1. The miR‐199a‐5p/ SIRT 1 pathway may thus represent a potential target for the prevention and treatment of epilepsy and epileptic damage.