Contribution of system xc- to generalized seizure generation in the pentylenetetrazole model

Joeri Van Liefferinge, Anneleen Schallier, Katrien Maes, Hideyo Sato, Yvette Michotte, Ilse Julia Smolders, Ann Massie

Research output: Contribution to journalMeeting abstract (Journal)

Abstract

Epilepsy is one of the most common neuro­logical dis­orders char­acter­ized by uncontrolled glu­tam­atergic neuro­trans­mission and oxi­dative stress (Costello & Delanty 2004). System xc- or the cystine/glu­tam­ate anti­porter ex­changes an in­tra­cellular glu­tam­ate mole­cule for an extra­cellular cystine mole­cule, thereby con­tri­buting to in­tra­cellular glutathione synthesis as well as non-vesicular glu­tam­ate release (Bannai 1986). System xc- could be of particular in­ter­est as a new target for treat­ment of epilepsy because of this dual role. Using respectively in vivo micro­dialysis and a quanti­tative colorimetric method, we in­ves­tigated the effect of xCT deletion on baseline cortical glu­tam­ate dialysate con­cen­trations and total glutathione content. Secondly, we studied the possible involvement of system xc- in generalized epilepsy by com­paring the susceptibility for PTZ-induced seizures be­tween xCT-/- and xCT+/+ mice. Basal extra­cellular glu­tam­ate levels in the frontal cortex of xCT-/- mice did not differ from those measured in xCT+/+ littermates, possibly in part due to the com­pen­satory in­crease in ex­pression level of VGLUT1 in the frontal cortex of the xCT-/- mice, as ob­served by semi-quanti­tative Western blotting. Total glutathione content is decreased in the frontal cortex of xCT-/- mice com­pared to their wildtype littermates. More­over, xCT-/- mice are more seizure-pro­ne in the PTZ model com­pared with their xCT+/+ littermates. To strengthen the find­ing that system xc- is implicated in generalized seizures, we used N-Ac, a pro­drug of cystine and activator of system xc- (De Bundel and Schallier et al. 2011). We ob­served that higher doses of PTZ are necessary to induce seizures in N-Ac-treated animals, com­pared with the control mice. It is known that non-vesicular glu­tam­ate release from system xc- stimulates extra­synaptic group II metabotropic glu­tam­ate (mGlu2/3) receptors (Baker et al. 2002) which func­tion as auto­receptors (Mateo & Porter 2007). How­ever, LY341495, a po­tent mGlu2/3 receptor antagonist, pre­treat­ment could not abolish the effect of N-Ac in the PTZ model, sug­gesting that activation of mGlu2/3 receptors is not the most important mecha­nism of altered seizure susceptibility in the N-Ac treated mice. Taken together, our results sug­gest a possible involvement of system xc- in the gene­ration of generalized seizures by regu­lating the synthesis of endo­genous glutathione in the pre­frontal cortex.
Original languageEnglish
Pages (from-to)122-122
Number of pages1
JournalJournal of Neurochemistry
Volume125
Issue numbers1
Publication statusPublished - 2013
EventThe 24th Biennial Meeting of the International Society for Neurochemistry and the American Society for Neurochemistry - Cancun, Mexico
Duration: 20 Apr 201324 Apr 2013

Keywords

  • system xc-
  • generalized seizures
  • pentylenetetrazole model
  • temporal lobe epilepsy

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