{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:29:14Z","timestamp":1785403754228,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T00:00:00Z","timestamp":1784419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002966","name":"Cumhuriyet University Scientific Research Projects","doi-asserted-by":"publisher","award":["T-521"],"award-info":[{"award-number":["T-521"]}],"id":[{"id":"10.13039\/501100002966","id-type":"DOI","asserted-by":"publisher"}]},{"award":["T-521"],"award-info":[{"award-number":["T-521"]}],"id":[{"id":"https:\/\/ror.org\/04f81fm77","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Patients with cerebrovascular disease frequently require concomitant antiplatelet and antiseizure therapy. However, experimental evidence regarding potential pharmacodynamic interactions between these medications remains limited. The present study investigated whether clopidogrel affects the anticonvulsant effects of valproic acid (VPA) or levetiracetam (LEV) in a pentylenetetrazol (PTZ)-induced seizure model. Forty-two male Wistar rats were randomly allocated to seven groups (n = 6\/group): Control, PTZ, clopidogrel (CLP), VPA, LEV, VPA + CLP + PTZ, and LEV + CLP + PTZ. Electroencephalographic recordings, passive avoidance testing, histopathological examination, and glial fibrillary acidic protein (GFAP) immunohistochemistry were performed to evaluate seizure activity, behavioral performance, neuronal injury, and astroglial activation. Both VPA and LEV significantly reduced spike\u2013wave discharge frequency and duration compared with the PTZ group (p &lt; 0.05). Clopidogrel alone did not exhibit anticonvulsant activity, and co-administration with either VPA or LEV did not significantly alter electrophysiological, behavioral, histopathological, or GFAP-associated immunohistochemical outcomes. Overall, these findings indicate that clopidogrel did not significantly affect the anticonvulsant efficacy of VPA or LEV under the experimental conditions of this acute PTZ-induced seizure model.<\/jats:p>","DOI":"10.3390\/ijms27146415","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6415","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of Clopidogrel on the Anticonvulsant Efficacy of Valproic Acid and Levetiracetam in a PTZ-Induced Seizure Model"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4671-0964","authenticated-orcid":false,"given":"Sibel","family":"\u00d6zdemir","sequence":"first","affiliation":[{"name":"Department of Neurology, Yunus Emre State Hospital, Eski\u015fehir 26140, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ertugrul","family":"Bolayir","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Cumhuriyet University, Sivas 58140, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep Deniz","family":"\u015eahin \u0130nan","sequence":"additional","affiliation":[{"name":"Department of Histology & Embryology, Faculty of Medicine, Cumhuriyet University, Sivas 58140, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1159\/000503831","article-title":"The epidemiology of epilepsy","volume":"54","author":"Beghi","year":"2020","journal-title":"Neuroepidemiology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"18-e3","DOI":"10.1111\/ene.13813","article-title":"Stroke-related epilepsy","volume":"26","author":"Feyissa","year":"2019","journal-title":"Eur. J. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1684\/epd.2020.1159","article-title":"How to diagnose and treat post-stroke seizures and epilepsy","volume":"22","author":"Zelano","year":"2020","journal-title":"Epileptic Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S1474-4422(15)00248-3","article-title":"Development of epilepsy after ischaemic stroke","volume":"15","author":"Roivainen","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.neuint.2017.02.002","article-title":"Post-stroke epilepsy","volume":"107","author":"Tanaka","year":"2017","journal-title":"Neurochem. Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S1474-4422(10)70310-0","article-title":"Mechanisms of epileptogenesis and potential treatment targets","volume":"10","author":"Lukasiuk","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1111\/epi.14550","article-title":"Activation of the innate immune system is evident throughout epileptogenesis and is associated with blood\u2013brain barrier dysfunction and seizure progression","volume":"59","author":"Broekaart","year":"2018","journal-title":"Epilepsia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e344","DOI":"10.1161\/STR.0000000000000211","article-title":"Guidelines for the Early Management of Patients with Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart Association\/American Stroke Association","volume":"50","author":"Powers","year":"2019","journal-title":"Stroke"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"CAPRIE Steering Committee (1996). A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet, 348, 1329\u20131339.","DOI":"10.1016\/S0140-6736(96)09457-3"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1161\/CIRCULATIONAHA.120.045465","article-title":"Antithrombotic therapy for atherosclerotic cardiovascular disease risk mitigation in patients with coronary artery disease and diabetes mellitus","volume":"142","author":"Capodanno","year":"2020","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1177\/1756285616654423","article-title":"Poststroke epilepsy: Update and future directions","volume":"9","author":"Zelano","year":"2016","journal-title":"Ther. Adv. Neurol. Disord."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1007\/s40262-013-0087-0","article-title":"Drug interactions with the newer antiepileptic drugs (AEDs)\u2014Part 1: Pharmacokinetic and pharmacodynamic interactions between AEDs","volume":"52","author":"Patsalos","year":"2013","journal-title":"Clin. Pharmacokinet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S1474-4422(03)00483-6","article-title":"Clinically important drug interactions in epilepsy: Interactions between antiepileptic drugs and other drugs","volume":"2","author":"Patsalos","year":"2003","journal-title":"Lancet Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1055\/s-2005-869523","article-title":"Clopidogrel and ticlopidine: P2Y12 adenosine diphosphate-receptor antagonists for the prevention of atherothrombosis","volume":"31","author":"Savi","year":"2005","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/S1474-4422(15)00314-2","article-title":"Valproic acid after five decades of use in epilepsy: Time to reconsider the indications of a time-honoured drug","volume":"15","author":"Tomson","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"707","DOI":"10.2165\/00003088-200443110-00002","article-title":"Clinical pharmacokinetics of levetiracetam","volume":"43","author":"Patsalos","year":"2004","journal-title":"Clin. Pharmacokinet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.yebeh.2008.05.012","article-title":"Positive and negative psychotropic effects of levetiracetam","volume":"13","author":"Helmstaedter","year":"2008","journal-title":"Epilepsy Behav."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.1016\/j.yebeh.2003.11.008","article-title":"Cognitive side effects of antiepileptic drugs","volume":"5","author":"Ortinski","year":"2004","journal-title":"Epilepsy Behav."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/nrd4126","article-title":"New avenues for anti-epileptic drug discovery and development","volume":"12","author":"Klitgaard","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0920-1211(02)00073-6","article-title":"Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs: A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy","volume":"50","year":"2002","journal-title":"Epilepsy Res."},{"key":"ref_21","first-page":"56573","article-title":"Pentylenetetrazole-Induced Kindling Mouse Model","volume":"12","author":"Shimada","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.yebeh.2016.01.032","article-title":"Evaluation of the pentylenetetrazole seizure threshold test in epileptic mice as surrogate model for drug testing against pharmacoresistant seizures","volume":"57","author":"Twele","year":"2016","journal-title":"Epilepsy Behav."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.2147\/NDT.S256117","article-title":"Effects of Levetiracetam Compared to Valproate on Cognitive Functions of Patients with Epilepsy","volume":"16","author":"Hamdi","year":"2020","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1007\/s11065-007-9043-9","article-title":"Neuropsychological and Behavioral Effects of Antiepilepsy Drugs","volume":"17","author":"Loring","year":"2007","journal-title":"Neuropsychol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S1474-4422(17)30404-0","article-title":"Prediction of late seizures after ischaemic stroke with a novel prognostic model (the SeLECT score): A multivariable prediction model development and validation study","volume":"17","author":"Galovic","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1016\/j.eplepsyres.2014.09.030","article-title":"Risk factors for post-stroke seizures: A systematic review and meta-analysis","volume":"108","author":"Zhang","year":"2014","journal-title":"Epilepsy Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.hlc.2014.01.005","article-title":"Clopidogrel improves microvascular endothelial function in subjects with stable coronary artery disease","volume":"23","author":"Willoughby","year":"2014","journal-title":"Heart Lung Circ."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1177\/0300985813485099","article-title":"Principles for valid histopathologic scoring in research","volume":"50","author":"Olivier","year":"2013","journal-title":"Vet. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1152\/physrev.00041.2013","article-title":"Astrocyte reactivity and reactive astrogliosis: Costs and benefits","volume":"94","author":"Pekny","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1177\/0271678X20943823","article-title":"The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research","volume":"40","author":"Hurst","year":"2020","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.neubiorev.2006.03.002","article-title":"Global and focal aspects of absence epilepsy: The contribution of genetic models","volume":"30","author":"Sitnikova","year":"2006","journal-title":"Neurosci. Biobehav. Rev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6415\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:40:34Z","timestamp":1784540434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6415"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,19]]},"references-count":31,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146415"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146415","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,19]]}}}