Interleukin-1β plays a role in the pathogenesis of mesial temporal lobe epilepsy through the PI3K/Akt/mTOR signaling pathway in hippocampal neurons

J Neuroimmunol. 2015 May 15;282:110-7. doi: 10.1016/j.jneuroim.2015.04.003. Epub 2015 Apr 2.

Abstract

Recently, the role of inflammation in the pathogenesis of mesial temporal lobe epilepsy (MTLE) has garnered great attention. Increasing evidence indicated that interleukin-1β (IL-1β) plays a critical role in the pathogenesis of MTLE. In this study, we cultured primary hippocampal neurons, using IL-1β to mimic the process of inflammatory reaction in neurons, then inhibited the inflammation using inhibitors of the PI3K/Akt/mTOR signaling pathway. The expression of proteins related to the PI3K/Akt/mTOR signaling pathway in rat hippocampal neurons was detected by western blot, and similar methods were applied to the hippocampi obtained from children with MTLE and normal controls. Neuronal somatic size and dendritic length were measured by immunohistochemistry and digital imaging. We observed that stimulation with IL-1β in neuron led to the up-regulation of p-Akt and p70S6K and promoted the growth of cell somatic size and dendritic length via the PI3K/Akt/mTOR signaling pathway. Pre-treatment with inhibitors of the pathway, LY294002 and rapamycin, decreased the expression of p-Akt and p70S6K and alleviated the morphological changes induced by IL-1β in hippocampal neurons. We further verified the increasement of P-Akt and p70S6K in the hippocampi of children with MTLE. These data are the first to demonstrate that the inflammatory response induced by IL-1β promotes seizures and plays an important role in the pathogenesis of MTLE via the PI3K/Akt/mTOR signaling pathway. Therefore, modulation of the PI3K/Akt/mTOR signaling pathway may be a novel therapeutic target for the treatment of MTLE.

Keywords: Epilepsy; Hippocampus; Inflammation; Interleukin-1β; MTLE; Neuron; Phosphatidylino-sitol 3-kinase; mTOR; p70S6K.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Child
  • Chromones / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Epilepsy, Temporal Lobe / pathology*
  • Female
  • Gene Expression Regulation / drug effects
  • Hippocampus / cytology*
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Humans
  • Interleukin-1beta / metabolism*
  • Interleukin-1beta / pharmacology
  • Male
  • Microtubule-Associated Proteins / metabolism
  • Morpholines / pharmacology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Oncogene Protein v-akt / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Chromones
  • Enzyme Inhibitors
  • Interleukin-1beta
  • MAP2 protein, rat
  • Microtubule-Associated Proteins
  • Morpholines
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • TOR Serine-Threonine Kinases
  • Oncogene Protein v-akt
  • Ribosomal Protein S6 Kinases, 70-kDa