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Leclercq, Karine; Liefferinge, Joeri Van; Albertini, Giulia; Neveux, Michel; Dardenne, Sylvia; Mairet‐Coello, Georges; Vandenplas, Catherine; Deprez, Tania; Chong, Seon‐Ah; Foerch, Patrik; Bentea, Eduard; Sato, Hideyo; Maher, Pamela; Massie, Ann; Smolders, Ilse; Kaminski, Rafal M.

Anticonvulsant and antiepileptogenic effects of system xc− inactivation in chronic epilepsy models

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  • Media type: E-Article
  • Title: Anticonvulsant and antiepileptogenic effects of system xc− inactivation in chronic epilepsy models
  • Contributor: Leclercq, Karine; Liefferinge, Joeri Van; Albertini, Giulia; Neveux, Michel; Dardenne, Sylvia; Mairet‐Coello, Georges; Vandenplas, Catherine; Deprez, Tania; Chong, Seon‐Ah; Foerch, Patrik; Bentea, Eduard; Sato, Hideyo; Maher, Pamela; Massie, Ann; Smolders, Ilse; Kaminski, Rafal M.
  • imprint: Wiley, 2019
  • Published in: Epilepsia
  • Language: English
  • DOI: 10.1111/epi.16055
  • ISSN: 1528-1167; 0013-9580
  • Keywords: Neurology (clinical) ; Neurology
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>The cystine/glutamate antiporter system could represent a new target for antiepileptogenic treatments due to its crucial roles in glutamate homeostasis and neuroinflammation. To demonstrate this, we compared epilepsy development and seizure susceptibility in <jats:styled-content style="fixed-case">xCT</jats:styled-content> knockout mice (<jats:styled-content style="fixed-case">xCT</jats:styled-content><jats:sup>−/−</jats:sup>) and in littermate controls (<jats:styled-content style="fixed-case">xCT</jats:styled-content><jats:sup>+/+</jats:sup>) in different chronic models of epilepsy.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Mice were surgically implanted with electrodes in the basolateral amygdala and chronically stimulated to develop self‐sustained status epilepticus (<jats:styled-content style="fixed-case">SSSE</jats:styled-content>); continuous video‐electroencephalography monitoring was performed for 28 days after <jats:styled-content style="fixed-case">SE</jats:styled-content> and hippocampal histopathology was assessed. Corneal kindling was induced by twice daily electrical stimulation at 6 Hz and maintenance of the fully kindled state was evaluated. Next, messenger RNA (<jats:styled-content style="fixed-case">mRNA</jats:styled-content>) and protein levels of <jats:styled-content style="fixed-case">xCT</jats:styled-content> and of the proteins involved in the phosphoinositide 3‐kinase (PI3K)/Akt/glycogen synthase kinase 3β (GSK‐3β)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4) signaling pathway were measured at different time points during epileptogenesis in <jats:styled-content style="fixed-case">NMRI</jats:styled-content> mice treated with pilocarpine. Finally, the anticonvulsant effect of sulfasalazine (<jats:styled-content style="fixed-case">SAS</jats:styled-content>), a nonselective system inhibitor, was assessed against 6 Hz‐evoked seizures in pilocarpine‐treated mice.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In the <jats:styled-content style="fixed-case">SSSE</jats:styled-content> model, <jats:styled-content style="fixed-case">xCT</jats:styled-content><jats:sup>−/−</jats:sup> mice displayed a significant delayed epileptogenesis, a reduced number of spontaneous recurrent seizures, and less pronounced astrocytic and microglial activation. Moreover, <jats:styled-content style="fixed-case">xCT</jats:styled-content><jats:sup>−/−</jats:sup> mice showed reduced seizure severity during 6 Hz kindling development and a lower incidence of generalized seizures during the maintenance of the fully kindled state. In pilocarpine‐treated mice, protein levels of the <jats:styled-content style="fixed-case">PI</jats:styled-content>3K/Akt/<jats:styled-content style="fixed-case">GSK</jats:styled-content>‐3β/<jats:styled-content style="fixed-case">eIF</jats:styled-content>2α/<jats:styled-content style="fixed-case">ATF</jats:styled-content>4 pathway were increased during the chronic phase of the model, consistent with previous findings in the hippocampus of patients with epilepsy. Finally, repeated administration of <jats:styled-content style="fixed-case">SAS</jats:styled-content> protected pilocarpine‐treated mice against acute 6 Hz seizure induction, in contrast to sham controls, in which system is not activated.</jats:p></jats:sec><jats:sec><jats:title>Significance</jats:title><jats:p>Inhibition of system could be an attractive target for the development of new therapies with a potential for disease modification in epilepsy.</jats:p></jats:sec>
  • Access State: Open Access