{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:35:51Z","timestamp":1785404151943,"version":"3.56.0"},"reference-count":91,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish \u201cConsejer\u00eda de Educaci\u00f3n de JCyL\u201d","award":["SA072G24"],"award-info":[{"award-number":["SA072G24"]}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["PI25\/01904"],"award-info":[{"award-number":["PI25\/01904"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"award":["PI25\/01904"],"award-info":[{"award-number":["PI25\/01904"]}],"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Experimental evidence indicates that a high seizure burden can induce cerebral overexpression of P-glycoprotein (P-gp) at the blood\u2013brain barrier, a phenomenon associated with drug-resistant epilepsy under the \u201ctransporter hypothesis\u201d, but also at the neuronal level, linked to a reduced seizure threshold, increased seizure severity (SS), status epilepticus (SE), and a high spontaneous death (SD) rate. In contrast, we recently described a progressive reduction in SS and the absence of SE and SD in GASH\/Sal hamsters subjected to 45 audiogenic seizures. Here, we examined SS, SE, and the SD, and the expression of P-gp, erythropoietin receptor (EPO-R), hypoxia-inducible factor 1 alpha subunit (HIF-1\u03b1) and cyclooxygenase 2 (COX-2), in the brains of GASH\/Sal hamsters following 20 audiogenic kindling stimulations (AUK-20). SS was evaluated using the midbrain and limbic severity scales; gene expression was assessed by RT-qPCR and P-gp protein levels were measured by immunohistochemistry and Western blot (IHC\/WB) analysis. A modest decrease in midbrain SS was observed, without an increase in the already low limbic SS scores, and no SE or SD events occurred. P-gp levels remained low in both IHC and WB analyses. At the mRNA level, we detected increased EPO-R expression, decreased HIF-1\u03b1, and increased COX-2 without an accompanying increased in Abcb1b. Unlike findings from other experimental epilepsy models, AUK-20 in GASH\/Sal hamsters does not enhance limbic SS, trigger SE or SD, or induce P-gp overexpression in the brain. Independently of the implications for drug resistance, the lack of cerebral P-gp overexpression without increased SS in the AUK-20-GASH\/Sal model supports a potential role of P-gp in modulating seizure severity and epilepsy-associated mortality risk.<\/jats:p>","DOI":"10.3390\/ijms27083377","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T12:21:32Z","timestamp":1775737292000},"page":"3377","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Audiogenic Kindling Stimulation Fails to Induce Cerebral Overexpression of P-Glycoprotein and Limbic Crises in the GASH\/Sal Model of Epilepsy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5323-4287","authenticated-orcid":false,"given":"Laura","family":"Zeballos","sequence":"first","affiliation":[{"name":"Instituto de Neurociencias de Castilla y Le\u00f3n (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"Departamento de Biolog\u00eda Celular y Patolog\u00eda, Facultad de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jer\u00f3nimo","family":"Auzmendi","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias de Castilla y Le\u00f3n (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Investigaciones Farmacol\u00f3gicas (ININFA, CONICET-UBA), Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Junin 956, Buenos Aires C1113, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Lazarowski","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias de Castilla y Le\u00f3n (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Fisiopatolog\u00eda y Bioqu\u00edmica Cl\u00ednica (INFIBIOC), Facultad de Farmacia y Bioqu\u00edmica, Universidad de Buenos Aires, Buenos Aires C1417, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1450-7246","authenticated-orcid":false,"given":"Dolores E.","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias de Castilla y Le\u00f3n (INCYL), Universidad de Salamanca, 37007 Salamanca, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca (IBSAL), 37007 Salamanca, Spain"},{"name":"Departamento de Biolog\u00eda Celular y Patolog\u00eda, Facultad de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1093\/jnci\/81.2.84","article-title":"Does P-Glycoprotein predict response to chemotherapy?","volume":"81","author":"Ling","year":"1989","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tang, F., Hartz, A.M.S., and Bauer, B. (2017). Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers. Front. Neurol., 8.","DOI":"10.3389\/fneur.2017.00301"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.neuroscience.2003.10.012","article-title":"Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures","volume":"123","author":"Volk","year":"2004","journal-title":"Neuroscience"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1046\/j.1528-1157.2003.42802.x","article-title":"Widespread upregulation of drug resistance proteins in fatal human status epilepticus","volume":"44","author":"Sisodiya","year":"2003","journal-title":"Epilepsia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1124\/mol.107.041210","article-title":"Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling","volume":"73","author":"Bauer","year":"2008","journal-title":"Mol. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1023\/B:CEMN.0000012726.43842.d2","article-title":"Neuronal and glial expression of the multidrug resistance gene product in an experimental epilepsy model","volume":"24","author":"Lazarowski","year":"2004","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/j.1528-1167.2007.01302.x","article-title":"ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy","volume":"48","author":"Lazarowski","year":"2007","journal-title":"Epilepsia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6732","DOI":"10.2174\/1381612811319380006","article-title":"P-glycoprotein contributes to cell membrane depolarization of hippocampus and neocortex in a model of repetitive seizures induced by pentylenetetrazole in rats","volume":"19","author":"Auzmendi","year":"2013","journal-title":"Curr. Pharm. Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1007\/s12031-022-02056-0","article-title":"The Prevention and Reversal of a Phenytoin-Resistant Model by N-acetylcysteine Therapy Involves the Nrf2\/P-Glycoprotein Pathway at the Blood-Brain Barrier","volume":"72","author":"Liu","year":"2022","journal-title":"J. Mol. Neurosci."},{"key":"ref_10","first-page":"43","article-title":"Progressive heart P- glycoprotein (P- gp) overexpression after experimental repetitive seizures (ERS) associated with fatal status epilepticus (FSE): Is it related with SUDEP?","volume":"1","author":"Auzmendi","year":"2014","journal-title":"Mol. Cell. Epilepsy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.phrs.2019.04.031","article-title":"ABC transporters in drug-resistant epilepsy: Mechanisms of upregulation and therapeutic approaches","volume":"144","author":"Leandro","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.neuropharm.2007.07.012","article-title":"Increased P-glycoprotein expression and decreased phenobarbital distribution in the brain of pentylenetetrazole-kindled rats","volume":"53","author":"Liu","year":"2007","journal-title":"Neuropharmacology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1124\/jpet.109.152520","article-title":"Targeting prostaglandin E2 EP1 receptors prevents seizure-associated P-glycoprotein up-regulation","volume":"330","author":"Pekcec","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fonseca-Barriendos, D., Casta\u00f1eda-Cabral, J.L., Mart\u00ednez-Cuevas, F., Besio, W., Vald\u00e9s-Cruz, A., and Rocha, L. (2023). Transcranial Focal Electric Stimulation Avoids P-Glycoprotein Over-Expression during Electrical Amygdala Kindling and Delays Epileptogenesis in Rats. Life, 13.","DOI":"10.3390\/life13061294"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Merelli, A., Ramos, A.J., Lazarowski, A., and Auzmendi, J. (2019). Convulsive Stress Mimics Brain Hypoxia and Promotes the P-Glycoprotein (P-gp) and Erythropoietin Receptor Overexpression. Recombinant Human Erythropoietin Effect on P-gp Activity. Front. Neurosci., 13.","DOI":"10.3389\/fnins.2019.00750"},{"key":"ref_16","first-page":"110810","article-title":"Influence of sex and age on the development of audiogenic kindling in the moderate seizure severity strain of the genetically epilepsy-prone rats","volume":"174","author":"Khandai","year":"2025","journal-title":"Epilepsy Behav."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"108846","DOI":"10.1016\/j.yebeh.2022.108846","article-title":"Dynamics of neurodegeneration in the hippocampus of Krushinsky-Molodkina rats correlate with the progression of limbic seizures","volume":"134","author":"Kulikov","year":"2022","journal-title":"Epilepsy Behav."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"147303","DOI":"10.1016\/j.brainres.2021.147303","article-title":"Cortical expression of IL1-\u03b2, Bcl-2, Caspase-3 and 9, SEMA-3a, NT-3 and P-glycoprotein as biological markers of intrinsic severity in drug-resistant temporal lobe epilepsy","volume":"1758","author":"Villa","year":"2021","journal-title":"Brain Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.jneumeth.2011.06.032","article-title":"Functional test of multidrug transporter activity in hippocampal-neocortical brain slices from epileptic patients","volume":"200","author":"Raue","year":"2011","journal-title":"J. Neurosci. Methods"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1093\/brain\/aws147","article-title":"Neuropathology of the blood-brain barrier and pharmaco-resistance in human epilepsy","volume":"135","author":"Liu","year":"2012","journal-title":"Brain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1146\/annurev-pharmtox-011112-140232","article-title":"Sodium channels, inherited epilepsy, and antiepileptic drugs","volume":"54","author":"Catterall","year":"2014","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e17984","DOI":"10.1016\/j.heliyon.2023.e17984","article-title":"Imbalance of glutamatergic and GABAergic neurotransmission in audiogenic seizure-susceptible Leucine-rich glioma-inactivated 1 (Lgi1) mutant rats","volume":"7","author":"Kinboshi","year":"2023","journal-title":"Heliyon"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.yebeh.2015.02.024","article-title":"An abnormal GABAergic system in the inferior colliculus provides a basis for audiogenic seizures in genetically epilepsy-prone rats","volume":"71","author":"Ribak","year":"2017","journal-title":"Epilepsy Behav."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"148792","DOI":"10.1016\/j.brainres.2024.148792","article-title":"Audiogenic kindling activates glutamatergic system in the hippocampus of rats with genetic predisposition to audiogenic seizures","volume":"1829","author":"Aleksandrova","year":"2024","journal-title":"Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/s42003-020-01538-4","article-title":"Voltage independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice","volume":"4","author":"Bertocchi","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1046\/j.1528-1157.2002.156702.x","article-title":"Regional expression of multidrug resistance genes in genetically epilepsy-prone rat brain after a single audiogenic seizure","volume":"43","author":"Kwan","year":"2002","journal-title":"Epilepsia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/epi.12182","article-title":"The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs","volume":"54","author":"Rogawski","year":"2013","journal-title":"Epilepsia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/ane.13115","article-title":"Drug-resistant epilepsy classified by a phenotyping algorithm associates with NTRK2","volume":"140","author":"Almoguera","year":"2019","journal-title":"Acta Neurol. Scand."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.neuroscience.2005.04.013","article-title":"Altered expression of GABA(A) and GABA(B) receptor subunit mRNAs in the hippocampus after kindling and electrically induced status epilepticus","volume":"134","author":"Nishimura","year":"2005","journal-title":"Neuroscience"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zeballos, L., Garc\u00eda-Peral, C., Ledesma, M.M., Auzmendi, J., Lazarowski, A., and L\u00f3pez, D.E. (2025). Changes in the Proteomic Profile After Audiogenic Kindling in the Inferior Colliculus of the GASH\/Sal Model of Epilepsy. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26052331"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"107973","DOI":"10.1016\/j.heares.2020.107973","article-title":"Morphological and molecular correlates of altered hearing sensitivity in the genetically audiogenic seizure-prone hamster GASH\/Sal","volume":"392","author":"Hyppolito","year":"2020","journal-title":"Hear. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.yebeh.2013.05.028","article-title":"Pharmacological and neuroethological study of three antiepileptic drugs in the genetic audiogenic seizure hamster (GASH:Sal)","volume":"28","author":"Oliveira","year":"2013","journal-title":"Epilepsy Behav."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.yebeh.2015.11.005","article-title":"Pharmacological validation of the genetic audiogenic seizure hamster (GASH:Sal) using several antiepileptics","volume":"71","author":"Oliveira","year":"2017","journal-title":"Epilepsy Behav."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Gon\u00e7alves-S\u00e1nchez, J., Ram\u00edrez-Santos, T., L\u00f3pez, D.E., Gon\u00e7alves-Estella, J.M., and Sancho, C. (2024). Assessing the Effectiveness of Eslicarbazepine Acetate in Reducing Audiogenic Reflex Seizures in the GASH\/Sal Model of Epilepsy. Biomedicines, 12.","DOI":"10.3390\/biomedicines12051121"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0920-1211(96)00050-2","article-title":"Neuroethological and morphological (Neo-Timm staining) correlates of limbic recruitment during the development of audiogenic kindling in seizure susceptible Wistar rats","volume":"26","author":"Wakamatsu","year":"1996","journal-title":"Epilepsy Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/0013-4694(72)90177-0","article-title":"Modification of seizure activity by electrical modification. II. Motor seizure","volume":"32","author":"Racine","year":"1972","journal-title":"Electroencephalogr. Clin. Neurophysiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.physbeh.2009.09.005","article-title":"A revised Racine\u2019s scale for PTZ-induced seizures in rats","volume":"98","author":"Fabene","year":"2009","journal-title":"Physiol. Behav."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.eplepsyres.2015.09.008","article-title":"Pilocarpine-induced status epilepticus in mice: A comparison of spectral analysis of electroencephalogram and behavioral grading using the Racine scale","volume":"117","author":"Phelan","year":"2015","journal-title":"Epilepsy Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.ibneur.2022.08.003","article-title":"Pentylenetetrazole kindling-induced epilepsy rat models: Insight on the severity state, a comparative study","volume":"13","author":"Ngoupaye","year":"2022","journal-title":"IBRO Neurosci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Jiang, M., and Wang, Y. (2025). Refinement of the pilocarpine-induced status epilepticus model in mice to improve mortality outcomes. Front. Neurosci., 19.","DOI":"10.3389\/fnins.2025.1592014"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1111\/j.1528-1167.2005.39404.x","article-title":"Brainstem seizure severity regulates forebrain seizure expression in the audiogenic kindling model","volume":"46","author":"Merrill","year":"2005","journal-title":"Epilepsia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"115233","DOI":"10.1016\/j.expneurol.2025.115233","article-title":"Decreased locus coeruleus multiunit activity in a mouse model of temporal lobe seizures with impaired consciousness","volume":"389","author":"Paszkowski","year":"2025","journal-title":"Exp. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0920-1211(00)00107-8","article-title":"Audiogenic kindling in the Wistar rat: A potential model for recruitment of limbic structures","volume":"39","year":"2000","journal-title":"Epilepsy Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/S0306-4522(96)00503-9","article-title":"The amygdala is critical for seizure propagation from brainstem to forebrain","volume":"77","author":"Hirsch","year":"1997","journal-title":"Neuroscience"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/S0006-8993(02)02884-6","article-title":"Synaptic plasticity in the pathway from the medial geniculate body to the lateral amygdala is induced by seizure repetition","volume":"946","author":"Feng","year":"2002","journal-title":"Brain Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"108445","DOI":"10.1016\/j.yebeh.2021.108445","article-title":"Audiogenic kindling stimulates aberrant neurogenesis, synaptopodin expression, and mossy fiber sprouting in the hippocampus of rats genetically prone to audiogenic seizures","volume":"125","author":"Kulikov","year":"2021","journal-title":"Epilepsy Behav."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e70020","DOI":"10.1002\/cpz1.70020","article-title":"Kindling Models of Epileptogenesis for Developing Disease-Modifying Drugs for Epilepsy","volume":"4","author":"Reddy","year":"2024","journal-title":"Curr. Protoc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"149294","DOI":"10.1016\/j.brainres.2024.149294","article-title":"Aging of Krushinsky-Molodkina audiogenic rats is accompanied with pronounced neurodegeneration and dysfunction of the glutamatergic system in the hippocampus","volume":"1846","author":"Aleksandrova","year":"2025","journal-title":"Brain Res."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Van Liefferinge, J., Massie, A., Portelli, J., Di Giovanni, G., and Smolders, I. (2013). Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?. Front. Cell. Neurosci., 7.","DOI":"10.3389\/fncel.2013.00139"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.eplepsyres.2017.08.010","article-title":"NTRK2 (TrkB gene) variants and temporal lobe epilepsy: A genetic association study","volume":"137","author":"Torres","year":"2017","journal-title":"Epilepsy Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/s12974-018-1245-y","article-title":"Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes","volume":"15","author":"Korotkov","year":"2018","journal-title":"J. Neuroinflamm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.jns.2016.06.031","article-title":"Evaluation of serum matrix metalloproteinase-3 as a biomarker for diagnosis of epilepsy","volume":"367","author":"Wang","year":"2016","journal-title":"J. Neurol. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/jnr.20387","article-title":"Metallothionein reduces central nervous system inflammation, neurodegeneration, and cell death following kainic acid-induced epileptic seizures","volume":"79","author":"Penkowa","year":"2005","journal-title":"J. Neurosci. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.eplepsyres.2017.02.021","article-title":"Increased metalloproteinase activity in the hippocampus following status epilepticus","volume":"132","author":"Dubey","year":"2017","journal-title":"Epilepsy Res."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Mohammed, A.R., Emam, W.A., Mohammed, S.A., Abd Elalim, A.A., Mansour, E.N.A., Nasr, H.M., Ghamry, A.A., Alkhawagah, S.M., Fathy, D.S.A., and Elattar, R.S. (2024). LncRNA ILF3AS1, MMP3, and MMP9 as well as miRNA-212 as emerging novel biomarkers for childhood epilepsy. Front. Mol. Biosci., 11.","DOI":"10.3389\/fmolb.2024.1434023"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Gon\u00e7alves-S\u00e1nchez, J., Sancho, C., L\u00f3pez, D.E., Castellano, O., Garc\u00eda-Cenador, B., Servilha-Menezes, G., Corchado, J.M., Garc\u00eda-Cairasco, N., and Gon\u00e7alves-Estella, J.M. (2023). Effect of Vagus Nerve Stimulation on the GASH\/Sal Audiogenic-Seizure-Prone Hamster. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010091"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.jneumeth.2008.04.019","article-title":"The pilocarpine model of temporal lobe epilepsy","volume":"172","author":"Curia","year":"2008","journal-title":"J. Neurosci. Methods"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1523\/JNEUROSCI.0980-08.2009","article-title":"Development of Spontaneous Recurrent Seizures after Kainate-Induced Status Epilepticus","volume":"29","author":"Williams","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.yebeh.2017.04.001","article-title":"The Wistar Audiogenic Rat (WAR) strain and its contributions to epileptology and related comorbidities: History and perspectives","volume":"71","author":"Umeoka","year":"2017","journal-title":"Epilepsy Behav."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.expneurol.2008.09.016","article-title":"Dissociation of seizure traits in inbred strains of mice using the flurothyl kindling model of epileptogenesis","volume":"215","author":"Papandrea","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.yebeh.2011.06.015","article-title":"Prevention of seizure-induced sudden death in a chronic SUDEP model by semichronic administration of a selective serotonin reuptake inhibitor","volume":"22","author":"Faingold","year":"2011","journal-title":"Epilepsy Behav."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.neuropharm.2009.01.009","article-title":"Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition","volume":"56","author":"Zibell","year":"2009","journal-title":"Neuropharmacology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1212\/01.WNL.0000042090.13247.48","article-title":"Evidence of cardiac ischemia during seizures in drug-refractory epilepsy patients","volume":"60","author":"Tigaran","year":"2003","journal-title":"Neurology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1111\/j.1528-1167.2009.02490.x","article-title":"How common is ictal hypoxemia and bradycardia in children with partial complex and generalized convulsive seizures?","volume":"51","author":"Moseley","year":"2010","journal-title":"Epilepsia"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"175","DOI":"10.4103\/1817-1745.193364","article-title":"Heart-type fatty acid-binding protein as a predictor of cardiac ischemia in intractable seizures in children","volume":"11","author":"Elsayed","year":"2016","journal-title":"J. Pediatr. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4304","DOI":"10.1073\/pnas.90.9.4304","article-title":"General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia","volume":"90","author":"Wang","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1101\/gad.14.16.1983","article-title":"HIF-1 and human disease: One highly involved factor","volume":"14","author":"Semenza","year":"2000","journal-title":"Genes Dev."},{"key":"ref_68","first-page":"1027","article-title":"HIF-1\u03b1 attenuates neuronal apoptosis by upregulating EPO expression following cerebral ischemia-reperfusion injury in a rat MCAO model","volume":"45","author":"Li","year":"2020","journal-title":"Int. J. Mol. Med."},{"key":"ref_69","first-page":"3387","article-title":"Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene","volume":"62","author":"Comerford","year":"2002","journal-title":"Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1097\/WNR.0000000000001345","article-title":"Involvement of hypoxia-inducible factor-1 alpha in the upregulation of P-glycoprotein in refractory epilepsy","volume":"30","author":"Wang","year":"2019","journal-title":"Neuroreport"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1111\/cns.13942","article-title":"Relationship between chronic hypoxia and seizure susceptibility","volume":"28","author":"Xu","year":"2022","journal-title":"CNS Neurosci. Ther."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1007\/s12035-025-05406-2","article-title":"The Role of HIF-1\u03b1\/BNIP3 Pathway in Hippocampal Neuronal Autophagy in Epilepsy","volume":"63","author":"Kuang","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.2174\/1381612826666200219095548","article-title":"EPO and EPO-Receptor System as Potential Actionable Mechanism for the Protection of Brain and Heart in Refractory Epilepsy and SUDEP","volume":"26","author":"Auzmendi","year":"2020","journal-title":"Curr. Pharm. Des."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.brainres.2014.09.028","article-title":"Hypoxia inducible factor-1\u03b1 expression is associated with hippocampal apoptosis during epileptogenesis","volume":"1590","author":"Long","year":"2014","journal-title":"Brain Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1159\/000438610","article-title":"Inhibiting HIF-1\u03b1 Decreases Expression of TNF-\u03b1 and Caspase-3 in Specific Brain Regions Exposed Kainic Acid-Induced Status Epilepticus","volume":"38","author":"Yang","year":"2016","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1093\/nar\/23.15.3041","article-title":"Regulation of transcription of the human erythropoietin receptor gene by proteins binding to GATA-1 and Sp1 motifs","volume":"23","author":"Chin","year":"1995","journal-title":"Nucleic Acids Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/35088074","article-title":"Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades","volume":"412","author":"Digicaylioglu","year":"2001","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1021\/acs.molpharmaceut.6b00770","article-title":"P-gp protein expression and transport activity in rodent seizure models and human epilepsy","volume":"14","author":"Hartz","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"106430","DOI":"10.1016\/j.yebeh.2019.07.031","article-title":"Drug-resistant epilepsy: From multiple hy-potheses to an integral explanation using preclinical resources","volume":"121","author":"Rocha","year":"2021","journal-title":"Epilepsy Behav."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Zhang, W., Liu, Q.Y., Haqqani, A.S., Liu, Z., Sodja, C., Leclerc, S., Baumann, E., Delaney, C.E., Brunette, E., and Stanimirovic, D.B. (2023). Differential Expression of ABC Transporter Genes in Brain Vessels vs. Peripheral Tissues and Vessels from Human, Mouse and Rat. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15051563"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Lazarowski, A. (2018). P-Glycoprotein Expression in Heart, and its Potential Physiological Relevance. J. Cardiol. Cardiovasc. Ther., 10.","DOI":"10.19080\/JOCCT.2018.10.555799"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Sun, X., Lv, Y., and Lin, J. (2023). The mechanism of sudden unexpected death in epilepsy: A mini review. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1137182"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/S0006-8993(97)00322-3","article-title":"Audiogenic kindling increases neuronal responses to acoustic stimuli in neurons of the medial geniculate body of the genetically epilepsy-prone rat","volume":"761","author":"Faingold","year":"1997","journal-title":"Brain Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/j.1749-6632.2001.tb05815.x","article-title":"Does the kindling model of epilepsy contribute to our understanding of multiple chemical sensitivity?","volume":"933","author":"Gilbert","year":"2001","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Damasceno, S., G\u00f3mez-Nieto, R., Garcia-Cairasco, N., Herrero-Turri\u00f3n, M.J., Mar\u00edn, F., and L\u00f3pez, D.E. (2020). Top common differentially expressed genes in the epileptogenic nucleus of two strains of rodents susceptible to audiogenic seizures: WAR and GASH\/Sal. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.00033"},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Fuerte-Hortig\u00f3n, A., Gon\u00e7alves, J., Zeballos, L., Masa, R., G\u00f3mez-Nieto, R., and L\u00f3pez, D.E. (2021). Distribution of the Cannabinoid Receptor Type 1 in the Brain of the Genetically Audiogenic Seizure-Prone Hamster GASH\/Sal. Front. Behav. Neurosci., 5.","DOI":"10.3389\/fnbeh.2021.613798"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4028","DOI":"10.1073\/pnas.94.8.4028","article-title":"Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins","volume":"94","author":"Schinkel","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Pappas, J.J., Petropoulos, S., Suderman, M., Iqbal, M., Moisiadis, V., Turecki, G., Matthews, S.G., and Szyf, M. (2014). The multidrug resistance 1 gene Abcb1 in brain and placenta: Comparative analysis in human and guinea pig. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111135"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Chapman, J.R., and Waldenstr\u00f6m, J. (2015). With reference to reference genes: A systematic review of endogenous controls in gene expression studies. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141853"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.yebeh.2016.05.040","article-title":"Morphofunctional alterations in the olivocochlear efferent system of the genetic audiogenic seizure-prone hamster GASH: Sal","volume":"71","author":"Murashima","year":"2017","journal-title":"Epilepsy Behav."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3377\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T04:45:15Z","timestamp":1775882715000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/8\/3377"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,9]]},"references-count":91,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijms27083377"],"URL":"https:\/\/doi.org\/10.3390\/ijms27083377","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,9]]}}}