MicroRNA expression profile of the hippocampus in a rat model of temporal lobe epilepsy and miR-34a-targeted neuroprotection against hippocampal neurone cell apoptosis post-status epilepticus

BMC Neurosci. 2012 Sep 22;13:115. doi: 10.1186/1471-2202-13-115.

Abstract

Background: The expression pattern and function of miRNAs in the rat model of temporal lobe epilepsy have not been well defined. Profiling miRNA expression in the rat model of temporal lobe epilepsy and investigating the function of specific miRNAs in epilepsy offers the prospect of a deeper understanding of the mechanisms of epilepsy.

Methods: The lithium-pilocarpine-induced status epilepticus model and the temporal lobe epilepsy model were established in Sprague-Dawley rats. Samples were analysed to detect deregulated miRNAs in the hippocampal temporal lobe, and several of these deregulated miRNAs were confirmed by qPCR. The expression of the pro-apoptotic miR-34a was detected at 1 day, 7 days and 2 weeks post-status epilepticus and at 2 months after temporal lobe epilepsy. The antagomir of miR-34a was then utilised. The expression of miR-34a after targeting and the expression change of activated caspase-3 protein were examined. The effects of altering the expression of miR-34a and activated caspase-3 protein on neuronal survival and neuronal death or apoptosis post-status epilepticus were assessed.

Results: The miRNA microarray detected 9 up-regulated miRNAs (miR-146a, -211, -203, -210, -152, -31, -23a, -34a, -27a) and 15 down-regulated miRNAs (miR-138*, -301a, -136, -153, -19a, -135b, -325-5p, -380, -190, -542-3p, -33, -144, -542-5p, -543, -296*). Some of the deregulated miRNAs (miR-146a, miR-210, miR-27a, miR-135b and miR-33) were confirmed using qPCR. Furthermore, an increase in expression of the pro-apoptotic miR-34a was demonstrated in the post-status epilepticus rat hippocampus. miR-34a was significantly up-regulated at 1 day, 7 days and 2 weeks post-status epilepticus and at 2 months after temporal lobe epilepsy. Experiments with the miR-34a antagomir revealed that targeting miR-34a led to an inhibition of activated caspase-3 protein expression, which may contribute to increased neuronal survival and reduced neuronal death or apoptosis.

Conclusions: Our study showed the expression profile of miRNAs in the hippocampus in a rat model of temporal lobe epilepsy and an increase in the expression of the pro-apoptotic miR-34a in post-status epilepticus rats. The results show that miR-34a is up-regulated during seizure-induced neuronal death or apoptosis, and targeting miR-34a is neuroprotective and is associated with an inhibition of an increase in activated caspase-3 protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Death / drug effects
  • Computational Biology
  • Disease Models, Animal
  • Epilepsy, Temporal Lobe / chemically induced
  • Epilepsy, Temporal Lobe / pathology*
  • Hippocampus / metabolism
  • Hippocampus / pathology*
  • In Situ Nick-End Labeling
  • Lithium / toxicity
  • Male
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Microarray Analysis
  • Neurons / metabolism*
  • Oligonucleotides / pharmacology
  • Pilocarpine / toxicity
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Status Epilepticus / chemically induced
  • Status Epilepticus / pathology*
  • Up-Regulation / drug effects

Substances

  • MIRN34 microRNA, rat
  • MicroRNAs
  • Oligonucleotides
  • RNA, Messenger
  • Pilocarpine
  • Lithium
  • Caspase 3