{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:16:02Z","timestamp":1760058962234,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T00:00:00Z","timestamp":1747353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Approximately one-third of epileptic patients do not respond adequately to drug therapy, leading to the development of drug-resistant epilepsy. Given the established role of dysregulated expression of two cation\u2013chloride cotransporter proteins, NKCC1 and KCC2, in susceptibility to convulsion generation and epilepsy development, the present study evaluates the anticonvulsant potential of bumetanide (BUM, 10 mg\/kg, i.p.) and probenecid (PROB, 50 mg\/kg, i.p.), the potential of adenosine receptor activation (NECA, 1 mg\/kg, i.p.) to modify the anticonvulsant efficacy of BUM, and the changes in NKCC1 and KCC2 protein expression levels in carbamazepine (CBZ)-resistant animals. In the window\u2013pentylenetetrazole (PTZ) kindling model, male Wistar rats that undergo full kindling develop CBZ-resistance. The combination of BUM + PROB appears to have an anticonvulsant effect on CBZ-resistant convulsions, while alterations in the protein levels of the NKCC1 and KCC2 cotransporters are observed in CBZ-resistant animals. Despite the absence of therapeutic efficacy in managing convulsions through adenosine receptor activation (BUM + NECA), the activation of adenosine receptors exhibits the capacity to modulate the levels of the NKCC1 protein in the hippocampus of CBZ-resistant animals. This effect provides the initial evidence for a new therapeutic role of adenosine receptors in regulating the pathological levels of NKCC1 in drug-resistant epilepsy.<\/jats:p>","DOI":"10.3390\/ijms26104764","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T05:11:57Z","timestamp":1747372317000},"page":"4764","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Evaluation of Cation\u2013Chloride Cotransporters NKCC1 and KCC2 in Carbamazepine-Resistant Rats"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0175-1511","authenticated-orcid":false,"given":"Cecilia","family":"Zavala-Tecuapetla","sequence":"first","affiliation":[{"name":"Experimental Laboratory of Neurodegenerative Diseases, National Institute of Neurology and Neurosurgery \u201cManuel Velasco Su\u00e1rez\u201d, Insurgentes Sur 3877, La Fama, Mexico City 14269, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5289-8500","authenticated-orcid":false,"given":"Sandra","family":"Orozco-Su\u00e1rez","sequence":"additional","affiliation":[{"name":"Medical Research Unit on Neurological Diseases, Specialty Hospital \u201cDr. Bernardo Sep\u00falveda\u201d, National Medical Center \u201cXXI Century\u201d, Mexican Social Security Institute, Av. Cuauht\u00e9moc 330, Doctores, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0089-5847","authenticated-orcid":false,"given":"Ang\u00e9lica","family":"Vega-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Medical Research Unit on Neurological Diseases, Specialty Hospital \u201cDr. Bernardo Sep\u00falveda\u201d, National Medical Center \u201cXXI Century\u201d, Mexican Social Security Institute, Av. Cuauht\u00e9moc 330, Doctores, Mexico City 06720, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joaqu\u00edn","family":"Manjarrez-Marmolejo","sequence":"additional","affiliation":[{"name":"Experimental Laboratory of Neurodegenerative Diseases, National Institute of Neurology and Neurosurgery \u201cManuel Velasco Su\u00e1rez\u201d, Insurgentes Sur 3877, La Fama, Mexico City 14269, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/epi.12550","article-title":"ILAE official report: A practical clinical definition of epilepsy","volume":"55","author":"Fisher","year":"2014","journal-title":"Epilepsia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1111\/j.1528-1167.2009.02397.x","article-title":"Definition of drug resistant epilepsy: Consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies","volume":"51","author":"Kwan","year":"2010","journal-title":"Epilepsia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1124\/pr.120.019539","article-title":"Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options","volume":"72","author":"Potschka","year":"2020","journal-title":"Pharmacol. 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