Anticonvulsant and Antiepileptogenic Effects of System xc-Inactivation in Chronic Epilepsy Models Leclercq K, Liefferinge JV, Albertini G, et al. Epilepsia. 2019. doi:10.1111/epi.16055. Epub ahead of print. PMID: 31179549Objective:The cystine/glutamate antiporter system xc- 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 xCT knockout mice (xCT−/−) and in littermate controls (xCT+/+) in different chronic models of epilepsy.Methods:Mice were surgically implanted with electrodes in the basolateral amygdala and chronically stimulated to develop self-sustained status epilepticus (SSSE); continuous video-electroencephalography monitoring was performed for 28 days after SE 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 (mRNA) and protein levels of xCT 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 Naval Medical Research Institute mice treated with pilocarpine. Finally, the anticonvulsant effect of sulfasalazine (SAS), a nonselective system xc-inhibitor, was assessed against 6 Hz-evoked seizures in pilocarpine-treated mice.Results:In the SSSE model, xCT−/− mice displayed a significant delayed epileptogenesis, a reduced number of spontaneous recurrent seizures, and less pronounced astrocytic and microglial activation. Moreover, xCT−/− 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 PI3K/Akt/GSK-3β/eIF2α/ATF4 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 SAS protected pilocarpine-treated mice against acute 6 Hz seizure induction, in contrast to sham controls, in which system xc- is not activated.Significance:Inhibition of system xc- could be an attractive target for the development of new therapies with a potential for disease modification in epilepsy. Decreased Epileptogenesis in Mice Lacking the System xc—Transporter Occurs in Association With a Reduction in AMPA Receptor Subunit GluA1 Sears SMS, Hewett JA, Hewett SJ. Epilepsia Open. 2019;4(1):133-143. doi:10.1002/epi4.12307. eCollection 2019 March. PMID: 30868123.Objective:Although the cystine/glutamate antiporter system xc—(Sxc-) plays a permissive role in glioma-associated seizures, its contribution to other acquired epilepsies has not been determined. As such, the present study investigates whether and how Sxc—contributes to the pentylenetetrazole (PTZ) chemical kindling model of epileptogenesis.Methods:Male Sxc—null (sut/sut) mice and their wild-type littermates were administered PTZ (intraperitoneal) daily for up to 21 days (kindling paradigm). Seizure severity was scored on a 5-point behavioral scale. Mossy fiber sprouting, cellular degeneration, and Sxc—light chain (xCT) messenger RNA (mRNA) were explored using Timm staining, thionin staining, and real-time quantitative polymerase chain reaction, respectively. Levels of reduced and oxidized glutathione and cysteine were determined via high-performance liquid chromatography. Plasma membrane protein levels of glutamate and γ-aminobutyric acid (GABA) receptor subunits as well as the K+/Cl− co-transporter KCC2 were quantified via Western blot analysis.Results:Repeated administration of PTZ produced chemical kindling in only 50% of Sxc—null mice as compared to 82% of wild-type littermate control mice. Kindling did not result in any changes in xCT mRNA levels assessed in wild-type mice. No cellular degeneration or mossy fiber sprouting was discernible in either genotype. Except for a small, but significant, decrease in oxidized cysteine in the hippocampus, no other change in measured redox couples was determined in Sxc - null mice. Cortical levels of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 were decreased in Sxc - null mice as compared to wild-type littermates, whereas all other proteins tested showed no difference between genotypes.Significance:This study provides the first evidence that Sxc-signaling contributes to epileptogenesis in the PTZ kindling model of acquired epilepsy. Further data indicate that a reduction in AMPA receptor signaling could underlie the resistance to PTZ kindling uncovered in Sxc-null mice.