Inflammatory changes during epileptogenesis and spontaneous seizures in a mouse model of mesiotemporal lobe epilepsy

Authors

  • Fabien Pernot,

    1. Department of Toxicology and Chemical Risks, Institut de Recherche Biomédicale des Armées, Centre de recherches du service de santé des armées, La Tronche Cedex, France
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    • Both authors equally contributed to this work.

  • Christophe Heinrich,

    1. Department of Physiological Genomics, Institute of Physiology, Ludwig-Maximilians Universität, Schillerstrasse, München, Germany
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    • Both authors equally contributed to this work.

  • Laure Barbier,

    1. Department of Toxicology and Chemical Risks, Institut de Recherche Biomédicale des Armées, Centre de recherches du service de santé des armées, La Tronche Cedex, France
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  • André Peinnequin,

    1. Department of Biological Effects of Radiation, Institut de Recherche Biomédicale des Armées, Centre de recherches du service de santé des armées, La Tronche Cedex, France
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  • Pierre Carpentier,

    1. Department of Toxicology and Chemical Risks, Institut de Recherche Biomédicale des Armées, Centre de recherches du service de santé des armées, La Tronche Cedex, France
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  • Franck Dhote,

    1. Department of Toxicology and Chemical Risks, Institut de Recherche Biomédicale des Armées, Centre de recherches du service de santé des armées, La Tronche Cedex, France
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  • Valérie Baille,

    1. Department of Toxicology and Chemical Risks, Institut de Recherche Biomédicale des Armées, Centre de recherches du service de santé des armées, La Tronche Cedex, France
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  • Claire Beaup,

    1. Department of Toxicology and Chemical Risks, Institut de Recherche Biomédicale des Armées, Centre de recherches du service de santé des armées, La Tronche Cedex, France
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  • Antoine Depaulis,

    1. Grenoble Institute of Neurosciences, Inserm U836-UJF-CEA, Chemin Fortuné Ferrini, Université Joseph Fourier, Site Santé, La Tronche Cedex, France
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  • Frédéric Dorandeu

    1. Department of Toxicology and Chemical Risks, Institut de Recherche Biomédicale des Armées, Centre de recherches du service de santé des armées, La Tronche Cedex, France
    2. Val-de-Grace School of Military Medicine, 1 place Alphonse Laveran, Paris, France
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Address correspondence to Fabien Pernot, PharmD, Ph.D., Rhenovia Pharma SAS, 20c rue de Chemnitz, 68100 Mulhouse, France. E-mail: fabien.pernot@gmail.com

Summary

Purpose:  Neuroinflammation appears as a prominent feature of the mesiotemporal lobe epilepsy syndrome (MTLE) that is observed in human patients and animal models. However, the precise temporal relationship of its development during epileptogenesis remains to be determined. The aim of the present study was to investigate (1) the time course and spatial distribution of neuronal death associated with seizure development, (2) the time course of microglia and astrocyte activation, and (3) the kinetics of induction of mRNAs from neuroinflammatory-related proteins during the emergence of recurrent seizures.

Methods:  Experimental MTLE was induced by the unilateral intrahippocampal injection of kainate in C57BL/6 adult mice. Microglial and astrocytic changes in both ipsilateral and contralateral hippocampi were examined by respectively analyzing griffonia simplicifolia (GSA) lectin staining and glial fibrillary acidic protein (GFAP) immunoreactivity. Changes in mRNA levels of selected genes of cytokine and cytokine regulatory proteins (interleukin-1β, IL-1β; interleukin-1 receptor antagonist, IL-1Ra; suppressor of cytokine signaling 3, SOCS3) and enzymes of the eicosanoid pathway (group IVA cytosolic phospholipase A2, cPLA2-α; cycloxygenase-2, COX-2) were studied by reverse transcription-quantitative real time polymerase chain reaction.

Key Findings:  Our data show an immediate cell death occurring in the kainate-injected hippocampus during the initial status epilepticus (SE). A rapid increase of activated lectin-positive cells and GFAP-immunoreactivity was subsequently detected in the ipsilateral hippocampus. In the same structure, Il-1β, IL-1Ra, and COX-2 mRNA were specifically increased during SE and epileptogenesis with a different time course. Conversely, the expression of SOCS3 mRNA, a surrogate marker of interleukin signaling, was mainly increased in the contralateral hippocampus after SE.

Significance:  Our data show that specific neuroinflammatory pathways are activated in a time- and structure-dependent manner with putative distinct roles in epileptogenesis.

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